55 results on '"Pawel Dokurno"'
Search Results
2. Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl‑2 and Mcl‑1
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James B. Murray, James Davidson, Ijen Chen, Ben Davis, Pawel Dokurno, Christopher J. Graham, Richard Harris, Allan Jordan, Natalia Matassova, Christopher Pedder, Stuart Ray, Stephen D. Roughley, Julia Smith, Claire Walmsley, Yikang Wang, Neil Whitehead, Douglas S. Williamson, Patrick Casara, Thierry Le Diguarher, John Hickman, Jerome Stark, András Kotschy, Olivier Geneste, and Roderick E. Hubbard
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Chemistry ,QD1-999 - Published
- 2019
- Full Text
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3. The Effect of Core Replacement on S64315, a Selective MCL‑1 Inhibitor, and Its Analogues
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I-Jen Chen, Proszenyák Ágnes, Zoltán B. Szabó, Levente Ondi, Csékei Márton, Olivier Geneste, Szabolcs Sipos, Allan E. Surgenor, Frédéric Colland, C. Pedder, Maïa Chanrion, Balázs Bálint, Ana-Leticia Maragno, Roderick E. Hubbard, Szlávik Zoltán, Pawel Dokurno, András Kotschy, James B. Murray, and James R. Davidson
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Cellular activity ,Pyrimidine ,Stereochemistry ,General Chemical Engineering ,General Chemistry ,Article ,chemistry.chemical_compound ,Chemistry ,chemistry ,In vivo ,Epimer ,Tumor growth ,Swap (computer programming) ,QD1-999 - Abstract
Following the identification of thieno[2,3-d]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable in vivo PD response. One compound was progressed into efficacy studies and inhibited tumor growth.
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- 2021
4. Design and Synthesis of Pyrrolo[2,3-d]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate
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Lindsey Terry, Victoria Chell, Samantha Newland, Pamela Acheson-Dossang, Douglas S. Williamson, Gitte Mikkelsen, Garrick Paul Smith, Allan E. Surgenor, Yikang Wang, Simon Bedford, Kenneth Vielsted Christensen, Pawel Dokurno, Lassina Badolo, Terry Shaw, Morten Hentzer, Stuart C. Ray, Chen I-Jen, and Thomas Jensen
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Pyrimidine ,Kinase ,Stereochemistry ,Mutant ,Leucine-rich repeat ,LRRK2 ,nervous system diseases ,chemistry.chemical_compound ,chemistry ,Protein kinase domain ,In vivo ,Drug Discovery ,Molecular Medicine ,CHEK1 - Abstract
Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18/CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] derivative 32. Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45, which demonstrated a favorable in vitro PK profile, although they displayed species disconnects in the in vivo PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.
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- 2021
5. Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B
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András Kotschy, Allan E. Surgenor, Andrea Fiumana, James Brooke Murray, Andrew Massey, Thomas Edmonds, Nicolas Foloppe, Didier Demarles, Pawel Dokurno, Mike Burbridge, Francisco Cruzalegui, K Benwell, Roderick E. Hubbard, Stuart C. Ray, Walmsley David, and Julia Smith
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Models, Molecular ,DYRK1B ,DYRK1A ,Cellular differentiation ,Mice, Nude ,Antineoplastic Agents ,Mice, SCID ,Protein Serine-Threonine Kinases ,01 natural sciences ,Metastasis ,Serine ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,030304 developmental biology ,Mice, Inbred BALB C ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,Brain Neoplasms ,Kinase ,Chemistry ,Neoplasms, Experimental ,Protein-Tyrosine Kinases ,medicine.disease ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Apoptosis ,Cancer research ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor - Abstract
The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.
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- 2021
6. Design and Synthesis of Pyrrolo[2,3
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Douglas S, Williamson, Garrick P, Smith, Gitte K, Mikkelsen, Thomas, Jensen, Pamela, Acheson-Dossang, Lassina, Badolo, Simon T, Bedford, Victoria, Chell, I-Jen, Chen, Pawel, Dokurno, Morten, Hentzer, Samantha, Newland, Stuart C, Ray, Terry, Shaw, Allan E, Surgenor, Lindsey, Terry, Yikang, Wang, and Kenneth V, Christensen
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Models, Molecular ,Structure-Activity Relationship ,HEK293 Cells ,Pyrimidines ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug Design ,Checkpoint Kinase 1 ,Humans ,Pyrroles ,Crystallography, X-Ray ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Protein Kinase Inhibitors - Abstract
Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3
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- 2021
7. Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors
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Attila Paczal, Thomas Edmonds, Nicolas Foloppe, Andrew Massey, András Kotschy, Mike Burbridge, Francisco Cruzalegui, Pawel Dokurno, Didier Demarles, Roderick E. Hubbard, Csaba Wéber, Sipos Melinda, Balázs Bálint, Vilibald Kun, K Benwell, James Murray, Walmsley David, and Alain Bruno
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DYRK1A ,Cell Survival ,Drug Evaluation, Preclinical ,Mice, Nude ,Protein Serine-Threonine Kinases ,01 natural sciences ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Adenosine Triphosphate ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Protein Isoforms ,Phosphorylation ,Protein Kinase Inhibitors ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,Binding Sites ,Chemistry ,Kinase ,Drug discovery ,Protein-Tyrosine Kinases ,Cyclin-Dependent Kinase 9 ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Pyrimidines ,Biochemistry ,Cell culture ,Drug Design ,Molecular Medicine ,Tumor growth inhibition ,Female ,Selectivity - Abstract
The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.
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- 2021
8. Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor
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Ana-Leticia Maragno, Attila Paczal, András Kotschy, Didier Demarles, James Edward Paul Davidson, Szlávik Zoltán, Allan E. Surgenor, Gaëtane Le Toumelin-Braizat, James Murray, Proszenyák Ágnes, Frédéric Colland, Gabor Radics, Szabolcs Sipos, Olivier Geneste, Balázs Bálint, Csékei Márton, Zoltán B. Szabó, Pawel Dokurno, Audrey Claperon, Anne-Marie Girard, Chen I-Jen, Alain Bruno, Gaëlle Lysiak-Auvity, Roderick E. Hubbard, Maïa Chanrion, and Zoe Daniels
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Myeloid ,Cell ,Antineoplastic Agents ,Mice, SCID ,01 natural sciences ,Protein Structure, Secondary ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Downregulation and upregulation ,Drug Discovery ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Dose-Response Relationship, Drug ,Cancer ,medicine.disease ,HCT116 Cells ,Small molecule ,0104 chemical sciences ,Protein Structure, Tertiary ,010404 medicinal & biomolecular chemistry ,Leukemia ,medicine.anatomical_structure ,Cell killing ,chemistry ,Cancer research ,Molecular Medicine ,Myeloid Cell Leukemia Sequence 1 Protein ,Female ,Lead compound ,HeLa Cells - Abstract
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
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- 2020
9. Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1)
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Chen I-Jen, Simon Bedford, Kenneth Vielsted Christensen, Victoria Chell, Allan E. Surgenor, Lindsey Terry, Justus Claus Alfred Daechsel, Kenneth Thirstrup, Samantha Newland, Jonathan D. Moore, Garrick Paul Smith, Pamela Acheson-Dossang, Martin C. Herzig, Stuart C. Ray, Zoe Daniels, Roderick E. Hubbard, James Brooke Murray, Douglas S. Williamson, Pawel Dokurno, Morten Hentzer, Yikang Wang, Terry Shaw, and Laurent David
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0301 basic medicine ,Protein domain ,Mutant ,Leucine-rich repeat ,Kidney ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,01 natural sciences ,Mice ,03 medical and health sciences ,Protein Domains ,Drug Discovery ,Animals ,Humans ,CHEK1 ,Protein Kinase Inhibitors ,Crystallography ,010405 organic chemistry ,Chemistry ,Kinase ,Brain ,Kidney metabolism ,Parkinson Disease ,LRRK2 ,Molecular biology ,nervous system diseases ,0104 chemical sciences ,HEK293 Cells ,030104 developmental biology ,Protein kinase domain ,Biochemistry ,Checkpoint Kinase 1 ,Mutation ,Molecular Medicine ,Protein Binding - Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson’s disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC50 data for 22 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-point mutant structure). Compound 22 was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LR...
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- 2017
10. Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity
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Didier Demarles, James Edward Paul Davidson, Levente Ondi, Allan E. Surgenor, Frédéric Colland, Attila Paczal, Marion Zarka, Alan P. Robertson, Zoltán B. Szabó, András Kotschy, Julia Smith, Perron-Sierra Françoise, Gabor Radics, Audrey Claperon, Ben Davis, Pawel Dokurno, Szlávik Zoltán, Csékei Márton, Gaetane LeToumelin-Braizat, Roderick E. Hubbard, Chen I-Jen, C. Pedder, Olivier Geneste, James Murray, and Nicolas Cauquil
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Cell Survival ,Cell ,Thiophenes ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Downregulation and upregulation ,Drug Discovery ,medicine ,Humans ,Caspase ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Drug discovery ,HCT116 Cells ,Small molecule ,0104 chemical sciences ,Amino acid ,Protein Structure, Tertiary ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Pyrimidines ,chemistry ,biology.protein ,Cancer research ,Molecular Medicine ,Myeloid Cell Leukemia Sequence 1 Protein ,Growth inhibition ,Lead compound ,HeLa Cells - Abstract
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.
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- 2019
11. Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1
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Pawel Dokurno, R. Harris, Patrick Casara, James Edward Paul Davidson, Olivier Geneste, Julia Smith, Douglas S. Williamson, Natalia Matassova, Yikang Wang, Allan M. Jordan, Stephen D. Roughley, András Kotschy, Roderick E. Hubbard, Jerome Stark, John A. Hickman, Chen I-Jen, Ben Davis, James Brooke Murray, C. Pedder, Walmsley Claire, Thierry Le Diguarher, Neil Whitehead, Stuart C. Ray, and Christopher John Graham
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Series (mathematics) ,Chemistry ,Drug discovery ,General Chemical Engineering ,Isothermal titration calorimetry ,General Chemistry ,Computational biology ,Small molecule ,Article ,Anti-Apoptotic Proteins ,lcsh:Chemistry ,Heteronuclear molecule ,lcsh:QD1-999 ,Surface plasmon resonance - Abstract
We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.
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- 2019
12. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
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James A. H. Murray, Fabien Melchiore, Natalia Matassova, C. Pedder, Frédéric Colland, Catherine Chang, Levente Ondi, Laura C. A. Galbraith, Pawel Dokurno, Andrew W. Roberts, Chris D. Riffkin, Nolwen Guigal-Stephan, Proszenyák Ágnes, John A. Hickman, Andreas Strasser, Aurélie Studeny, Gaëlle Lysiak-Auvity, András Kotschy, Gemma L. Kelly, Fabienne Gravé, Ghislaine Guasconi, Brandon J. Aubrey, Attila Paczal, Julia Smith, Szlávik Zoltán, Gabor Radics, Brian Lockhart, David C.S. Huang, Maïa Chanrion, Gaëtane Le Toumelin-Braizat, Jia-Nan Gong, Nicolas Cauquil, Szabolcs Sipos, Alan P. Robertson, Giovanna Pomilio, James Edward Paul Davidson, Zoltán B. Szabó, Ana Leticia Maragno, Chris Graham, Marco J Herold, Gábor Blasko, Margs S. Brennan, Anne-Marie Girard, Allan E. Surgenor, Andrew H. Wei, Csékei Márton, Olivier Geneste, Chen I-Jen, Alain Bruno, David J. Segal, Guillaume Lessene, Balázs Bálint, and Donia M Moujalled
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Male ,Models, Molecular ,0301 basic medicine ,Lymphoma ,Antineoplastic Agents ,Apoptosis ,Bcl-xL ,Thiophenes ,Pharmacology ,Models, Biological ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Bcl-2-associated X protein ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,MCL1 ,bcl-2-Associated X Protein ,Leukemia ,Multidisciplinary ,biology ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Myeloid Cell Leukemia Sequence 1 Protein ,Pyrimidines ,bcl-2 Homologous Antagonist-Killer Protein ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Female ,Multiple Myeloma ,Bcl-2 Homologous Antagonist-Killer Protein - Abstract
Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.
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- 2016
13. S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth
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Patrick Casara, James Davidson, Audrey Claperon, Gaëtane Le Toumelin-Braizat, Meike Vogler, Alain Bruno, Maïa Chanrion, Gaëlle Lysiak-Auvity, Thierry Le Diguarher, Jérôme-Benoît Starck, Ijen Chen, Neil Whitehead, Christopher Graham, Natalia Matassova, Pawel Dokurno, Christopher Pedder, Youzhen Wang, Shumei Qiu, Anne-Marie Girard, Emilie Schneider, Fabienne Gravé, Aurélie Studeny, Ghislaine Guasconi, Francesca Rocchetti, Sophie Maïga, Jean-Michel Henlin, Frédéric Colland, Laurence Kraus-Berthier, Steven Le Gouill, Martin J.S. Dyer, Roderick Hubbard, Mike Wood, Martine Amiot, Gerald M Cohen, John A. Hickman, Erick Morris, James Murray, Olivier Geneste, Institut de Recherches Servier, Vernalis (R&D) Ltd, Institute for Experimental Cancer Research in Pediatrics, Goethe-Universität Frankfurt am Main, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Novartis Institute of Biomedical Research, Oncology Drug Discovery, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Ernest and Helen Scott Haematological Research Institute, University of Leicester, Institute of Translational Medicine, University of Liverpool, Goethe-University Frankfurt, Institut de Recherches Internationales Servier [Suresnes] ( IRIS ), Regulation of Bcl2 and p53 networks in Multiple Myeloma and Mantle Cell Lymphoma ( CRCINA - Département NOHMAD - Equipe 10 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
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0301 basic medicine ,apoptosis ,BCL-2 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,BH3-mimetics ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,3. Good health ,inhibitor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Oncology ,030220 oncology & carcinogenesis ,hematological malignancies ,Research Paper - Abstract
International audience; Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, welltolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.
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- 2018
14. Abstract 4482: S64315 (MIK665) is a potent and selective Mcl1 inhibitor with strong antitumor activity across a diverse range of hematologic tumor models
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Audrey Clapéron, Balázs Bálint, Chen I-Jen, Alain Bruno, Attila Paczal, Szlávik Zoltán, Zoltán B. Szabó, Ensar Halilovic, Heiko Maacke, Alix Derreal, James Edward Paul Davidson, Maïa Chanrion, Ana Leticia Maragno, Szabolcs Sipos, Fabienne Grave, Olivier Geneste, James Murray, Proszenyák Ágnes, Youzhen Wang, Natalia Matassova, Pawel Dokurno, Allan E. Surgenor, Csékei Márton, Prakash Mistry, András Kotschy, Gaëtane Le Toumelin-Braizat, Erick Morris, Frédéric Colland, Anne-Marie Girard, and Gaëlle Lysiak-Auvity
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0301 basic medicine ,Cancer Research ,business.industry ,Venetoclax ,Cancer ,Myeloid leukemia ,medicine.disease ,Lymphoma ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Cell killing ,Oncology ,chemistry ,Apoptosis ,In vivo ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,Cancer research ,business - Abstract
Mcl-1 is highly expressed in a variety of human cancers (including those of hematopoietic and lymphoid origin) and is exploited by cancer cells to evade cell death and to develop resistance to diverse chemotherapeutic agents. We disclose, for the first time, the structure of S64315 (also named MIK665) a highly potent and selective inhibitor of Mcl-1 with improved potency over its predecessor S63845 (Kotschy et al, Nature, 2016). S64315/MIK665 is currently in phase 1 in AML (Acute Myeloid Leukemia) and MDS (Myelodysplastic Syndrome) (EudraCT 2016-003768-38, NCT 02979366) and in MM (Multiple Myeloma) and lymphoma (NCT02992483). A fragment-based, structure-guided drug discovery effort led to the identification of S64315/MIK665 that binds to human Mcl-1 with a sub-nanomolar affinity (Ki 0.048 nM) and selectively over other anti-apoptotic Bcl-2 family members. It has similar affinity for human, rat, dog and monkey Mcl-1 but about a ten-fold lower affinity for mouse Mcl-1. S64315/MIK665 causes dose-dependent activation of the intrinsic apoptosis pathway in a Bax/Bak-dependent manner, as measured by increased caspase activity and cleaved PARP. S64315/MIK665 shows strong cell killing activity in a diverse panel of human hematological tumor cell lines, including AML, lymphoma and MM. The activity profile of S64315/MIK665 is distinct from that of venetoclax, a selective Bcl2 inhibitor. In vivo, S64315 as single agent demonstrated potent and dose-dependent apoptotic and antitumor response after intravenous administration in several human hematological tumor models grafted in immuno-compromised mice and rats. Complete regression of established tumors, at well tolerated doses, was achieved using different intravenous dosing regimens in rats as well as in mice. Finally, dual BH3-mimetic targeting approach combining S64315/MIK665 with BCL2 inhibitors showed strong and durable antitumor responses in several hematological tumor models both in vitro and in vivo. Citation Format: Ana Leticia Maragno, Prakash Mistry, András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Alain Bruno, Audrey Claperon, Heiko Maacke, Erick Morris, Youzhen Wang, Alix Derreal, Márton Csekei, Attila Paczal, Zoltán Szabo, Szabolcs Sipos, Agnes Proszenyak, Balázs Balint, Allan Surgenor, Pawel Dokurno, Natalia Matassova, Ijen Chen, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Grave, Frédéric Colland, Ensar Halilovic, Olivier Geneste. S64315 (MIK665) is a potent and selective Mcl1 inhibitor with strong antitumor activity across a diverse range of hematologic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4482.
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- 2019
15. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution
- Author
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David A. Robinson, Claire L. Nunns, Christopher J. Northfield, Jonathan D. Moore, Christine M. Richardson, Ben Davis, James Brooke Murray, Victoria Oldfield, Pawel Dokurno, Simon F. Scrace, Lisa Baker, Stuart C. Ray, Christophe Fromont, Allan E. Surgenor, Natalia Matossova, Andrew John Potter, and Christopher J. Bryant
- Subjects
Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Cell ,Pharmaceutical Science ,Isomerase ,Biochemistry ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Humans ,Imidazole ,Threonine ,NIMA-Interacting Peptidylprolyl Isomerase ,Molecular Biology ,Molecular Structure ,Kinase ,Drug discovery ,Organic Chemistry ,Imidazoles ,Peptidylprolyl Isomerase ,medicine.anatomical_structure ,chemistry ,PIN1 ,Molecular Medicine ,Caco-2 Cells - Abstract
Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential.
- Published
- 2010
16. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells
- Author
-
Stephanie Geoffroy, Martin J. Drysdale, Pawel Dokurno, Zoe Daniels, James Brooke Murray, Paul Lavan, Geraint L. Francis, Natalia Matassova, Rachel Parsons, Douglas S. Williamson, Melanie Dopson, Terry Shaw, Yikang Wang, Antony Padfield, Mike Comer, Andrew Massey, Macias Alba, Michael Wood, Christopher John Graham, Helen Browne, and Vernalis (R&D) Ltd
- Subjects
Cancer Research ,Programmed cell death ,Breast Neoplasms ,Hsp90 ,Apoptosis ,Protein degradation ,Biology ,Toxicology ,Combination studies ,Hsp70 ,Hsp90 inhibitor ,Drug Delivery Systems ,Hsc70 ,Cell Line, Tumor ,Heat shock protein ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,HSP70 Heat-Shock Proteins ,Pharmacokinetics ,Pharmacology (medical) ,HSP90 Heat-Shock Proteins ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,Caspase 7 ,Pharmacology ,Inhibitor of apoptosis domain ,Caspase 3 ,Cell growth ,HSC70 Heat-Shock Proteins ,Drug Synergism ,Purine Nucleosides ,Small molecule ,Oncology ,Colonic Neoplasms ,Immunology ,Cancer research ,Female ,Small molecule inhibitor - Abstract
The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition.We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors.VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level.These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined.
- Published
- 2009
17. Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping
- Author
-
Philip Stephen Jackson, Douglas S. Williamson, Martin J. Drysdale, Claire L. Nunns, Roderick E. Hubbard, Rob Howes, Harry Finch, Peter Kierstan, Martin J. Parratt, Jonathan D. Moore, Allan E. Surgenor, Heather Simmonite, Christopher J. Torrance, Georg Lentzen, Christine M. Richardson, Jenifer Borgognoni, Pawel Dokurno, and James Brooke Murray
- Subjects
Virtual screening ,biology ,Molecular model ,Chemistry ,Stereochemistry ,Cyclin-Dependent Kinase 2 ,Organic Chemistry ,Clinical Biochemistry ,Cyclin-dependent kinase 2 ,Rational design ,Pharmaceutical Science ,Crystal structure ,Crystallography, X-Ray ,Biochemistry ,Cyclin-dependent kinase ,Docking (molecular) ,Drug Design ,Drug Discovery ,biology.protein ,Molecular Medicine ,Kinase binding ,Protein Kinase Inhibitors ,Molecular Biology - Abstract
Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.
- Published
- 2007
18. Molecular Basis of AKAP Specificity for PKA Regulatory Subunits
- Author
-
Kjetil Taskén, Pawel Dokurno, Birgitte Lygren, Matthew G. Gold, Naoto Hoshi, Cathrine Rein Carlson, John D. Scott, David Barford, and George McConnachie
- Subjects
Models, Molecular ,Gene isoform ,A-kinase-anchoring protein ,endocrine system ,Protein subunit ,Molecular Sequence Data ,Peptide ,Biology ,Crystallography, X-Ray ,Protein Structure, Secondary ,Substrate Specificity ,A Kinase Anchor Proteins ,Mice ,Apoenzymes ,Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit ,Animals ,Humans ,Amino Acid Sequence ,Protein kinase A ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,chemistry.chemical_classification ,Binding Sites ,Cell Biology ,Cyclic AMP-Dependent Protein Kinases ,Protein Subunits ,chemistry ,Structural biology ,Biochemistry ,Docking (molecular) ,Biophysics ,Cattle ,Peptides ,Dimerization ,Hydrophobic and Hydrophilic Interactions ,Sequence Alignment ,Protein Binding - Abstract
Summary Localization of cyclic AMP (cAMP)-dependent protein kinase (PKA) by A kinase-anchoring proteins (AKAPs) restricts the action of this broad specificity kinase. The high-resolution crystal structures of the docking and dimerization (D/D) domain of the RIIα regulatory subunit of PKA both in the apo state and in complex with the high-affinity anchoring peptide AKAP- IS explain the molecular basis for AKAP-regulatory subunit recognition. AKAP- IS folds into an amphipathic α helix that engages an essentially preformed shallow groove on the surface of the RII dimer D/D domains. Conserved AKAP aliphatic residues dominate interactions to RII at the predominantly hydrophobic interface, whereas polar residues are important in conferring R subunit isoform specificity. Using a peptide screening approach, we have developed SuperAKAP- IS , a peptide that is 10,000-fold more selective for the RII isoform relative to RI and can be used to assess the impact of PKA isoform-selective anchoring on cAMP-responsive events inside cells.
- Published
- 2006
19. Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: Protein structure-guided design and SAR
- Author
-
Allan E. Surgenor, James B. Murray, Alan Robertson, Martin J. Parratt, Andrew Cansfield, Christopher J. Torrance, Pawel Dokurno, Jenifer Borgognoni, Jonathan D. Moore, Christine M. Richardson, Douglas S. Williamson, Geraint L. Francis, and Rob Howes
- Subjects
Molecular model ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,GSK-3 ,Cell Line, Tumor ,Drug Discovery ,Humans ,Structure–activity relationship ,Protein kinase A ,Glycogen synthase ,Protein Kinase Inhibitors ,Molecular Biology ,Molecular Structure ,biology ,Chemistry ,Cyclin-Dependent Kinase 2 ,Organic Chemistry ,Cyclin-dependent kinase 2 ,Triazoles ,Pyrimidines ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Selectivity - Abstract
Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3beta (GSK-3beta). One example had a CDK2 IC(50) of 120 nM and showed selectivity over GSK-3beta of 167-fold.
- Published
- 2006
20. Synthesis, X-ray structure and high-resolution NMR spectroscopy of methyl 3-azido-2,3-dideoxy-α-d-arabino-hexopyranoside
- Author
-
Pawel Dokurno, Aleksandra Dąbrowska, Antoni Konitz, and Zygfryd Smiatacz
- Subjects
Models, Molecular ,Azides ,Magnetic Resonance Spectroscopy ,High resolution nmr ,Chemistry ,Stereochemistry ,Organic Chemistry ,Carbohydrates ,X-ray ,Hydrogen Bonding ,General Medicine ,Crystal structure ,Carbon-13 NMR ,Crystallography, X-Ray ,Biochemistry ,Analytical Chemistry ,Crystallography ,X-ray crystallography ,Molecule ,Glycosides ,Spectroscopy - Abstract
The synthesis, crystal structure data and 1 H and 13 C NMR spectroscopy of methyl 3-azido-2,3-dideoxy-α- d - arabino -hexopyranoside ( 5b ) is reported. This compound adopts the 4 C 1 conformation. Hydrogen-bonded molecules of 5b form helices around the crystallographic 4 1 axis.
- Published
- 1999
21. Conformational analysis of the first observed non-proline cis-peptide bond occurring within the complementarity determining region (CDR) of an antibody
- Author
-
Michael J.E. Sternberg, Pawel Dokurno, Paul S. Freemont, and Paul A. Bates
- Subjects
Models, Molecular ,chemistry.chemical_classification ,Databases, Factual ,Proline ,Protein Conformation ,Stereochemistry ,Immunoglobulin Variable Region ,Protein Data Bank (RCSB PDB) ,Peptide ,Peptide binding ,Complementarity determining region ,Crystallography, X-Ray ,Antibodies ,Peptide Conformation ,Loop (topology) ,Crystallography ,Protein structure ,chemistry ,Structural Biology ,Peptide bond ,Peptides ,Molecular Biology - Abstract
An analysis has been performed on the first example of a non-proline cis- peptide bond found within a complementarity determining region (CDR) of an antibody. The bond is located in CDR 3 of the heavy chain (H3) and makes substantial interactions to a peptide from a breast tumour-associated antigen. The antibody-peptide complex is compared, both in H3 length (six residues) and peptide conformation, to a number of other such complexes in the Brookhaven Data Bank (PDB). There is only one other H3 loop of the same length. Analysis of loop searches of the PDB, taken over the H3 framework of SM3, suggest that there is a limited repertoire of conformations for loops of length 6 compared to loops of length 5 and 7. It is argued that the cis-peptide bond is present because of the limited number of loop conformations of length 6, plus, the requirement of the H3 loop to contact the bound peptide. Modelling suggests that an all-trans-peptide loop conformation can replace the H3 loop and this raises the question of whether there is a trans- to cis-peptide bond isomerization upon peptide binding.
- Published
- 1998
22. Crystal structure at 1.95 å resolution of the breast tumour-specific antibody SM3 complexed with its peptide epitope reveals novel hypervariable loop recognition
- Author
-
John M. Lally, Joyce Taylor-Papadimitriou, Paul S. Freemont, Joy Burchell, H.A. Band, David Snary, Michael J.E. Sternberg, Lorna M. Stewart, Paul A. Bates, and Pawel Dokurno
- Subjects
Models, Molecular ,chemistry.chemical_classification ,Antibodies, Neoplasm ,Mucins ,Breast Neoplasms ,Peptide ,Biology ,Immunoglobulin light chain ,Epitope ,Antigen-Antibody Reactions ,Epitopes ,Immunoglobulin Fab Fragments ,chemistry ,Antigen ,Biochemistry ,Structural Biology ,Molecular replacement ,Amino Acid Sequence ,Peptides ,Molecular Biology ,Protein secondary structure ,Peptide sequence ,MUC1 - Abstract
The anti-breast tumour antibody SM3 has a high selectivity in reacting specifically with carcinoma-associated mucin. SM3 recognises the core repeating motif (Pro-Asp-Thr-Arg-Pro) of aberrantly glycosylated epithelial mucin MUC1, and has potential as a therapeutic and diagnostic tool. Here we report the crystal structure of the Fab fragment of SM3 in complex with a 13-residue MUC1 peptide antigen (Thr1P-Ser2P-Ala3P-Pro4P-Asp5P-Thr6P -Arg7P-Pro8P-Ala9P-Pro10P-Gly11P- Ser12P-Thr13P). The SM3-MUC1 peptide structure was solved by molecular replacement, and the current model is refined at 1.95 A resolution with an R-factor of 21.3% and R-free 28.3%. The MUC1 peptide is bound both by non-polar interactions and hydrogen bonds in an elongated groove in the antibody-combining site through interactions with Complimentarity Determining Regions (CDRs), three of the light chain (L1, L2, L3) and two of the heavy chain (H1 and H3). The conformation of the peptide is mainly extended with no discernable standard secondary structure. There is a single non-proline cis-peptide bond in H3 (Val95H-Gly96H-Gln97H-Phe98H-Ala101H-Ty r102H) between Gly96H and Gln97H, which appears to play a role in SM3-peptide antigen interactions, and represents the first such example within an antibody hypervariable loop. The SM3-MUC1 peptide structure has implications for rational therapeutic and diagnostic antibody engineering.
- Published
- 1998
23. Crystal Structure of 9(10-Methyl)- Acridinimine Hydriodide. Lattice Energetics of this Compound and Halide Salts of Nitrogen Organic Bases
- Author
-
Karol Krzymiń Ski, Jerzy Błażejowskia, Jacek Rulewski, Pawel Dokurno, Janusz Rak, and Antoni Konitz
- Subjects
chemistry.chemical_classification ,Lattice energy ,Double bond ,Halide ,Crystal structure ,Condensed Matter Physics ,Tautomer ,Crystallography ,chemistry.chemical_compound ,chemistry ,Computational chemistry ,Acridine ,Molecule ,Monoclinic crystal system - Abstract
The crystal structure of hydriodide of 9(10-methyl)-acridinimine, the cation of which originates from the imino tautomeric form of 9-acridinamine, was determined by X-ray analysis (monoclinic; space group P21/c; Z=4; R=0.0368 for 1651 observed reflections). The bond between the egzocyclic N atom and the acridine moiety retains a length typical for double bonds, while lengths of adjacent C-C bonds are contained between those characteristic for single and aromatic bonds. The central ring system is strongly conjugated with the side rings through bonds at the endocyclic N atom which results in the acridine skeleton being almost planar. For this molecule and fifteen halide salts of simple nitrogen organic bases, the electrostatic, dispersive and repulsive contributions to the lattice energy were evaluated, boiling down the problem of intermolecular interactions to atom - atom interactions. Coulombic energies arising from charges fitted to the molecular electrostatic potential on the DFT level, compare...
- Published
- 1996
24. Thermal behaviour of organochlorine pesticides in the presence of alkaline substances
- Author
-
Jerzy Błażejowski, Ludwika Gruzdiewa, Janusz Rak, and Pawel Dokurno
- Subjects
Potassium carbonate ,chemistry.chemical_compound ,Reaction mechanism ,Volatilisation ,chemistry ,Inorganic chemistry ,Methoxychlor ,Pesticide ,Thermal analysis ,Lindane ,Decomposition - Abstract
Selected organochlorine pesticides, namely lindane, PCNB,p,p′-DDT andp,p′-methoxychlor, and some related compounds (p,p′-DDE andp,p′-DMDE) were heated in the presence of powdered KOH, Na2CO3, CaO and CaCO3 in order to check whether degradation of the compounds is feasible in moderate conditions and temperatures. Thermal analyses, as well as investigations concerning the search for the reaction products revealed that processes occurring at atmospheric pressure are either simple volatilization of organic molecules, observed upon heating of mixtures containing lindane, PCNB,p,p′-DDE andp,p′-DMDE, or volatilization accompanied with decomposition towards HCl andp,p′-DDE andp,p′-DMDE, noted when heating mixtures ofp,p′-DDT andp,p′-methoxychlor with alkaline substances, respectively. Complementary theoretical calculations enabled insight into the mechanism of HCl elimination fromp,p′-DDT andp,p′-methoxychlor.
- Published
- 1995
25. Theoretical prediction of enthalpies and temperatures of sublimation of organochlorine compounds including pesticides
- Author
-
Pawel Dokurno, Janusz Rak, Piotr Skurski, Jacek Rulewski, and Jerzy Błażejowski
- Subjects
Lattice energy ,Volatilisation ,Enthalpy of sublimation ,Chemistry ,Enthalpy ,Thermodynamics ,Zero-point energy ,Sublimation (phase transition) ,Crystal structure ,Pesticide - Abstract
Crystal lattice energies of several organochlorine compounds—including pesticides, of known crystal structures were calculated on the basis of a model which takes into account electrostatic, dispersive and repulsive interactions—using three different sets of empirical parameters. These characteristics compare reasonably with experimental heats of volatilization, and it was subsequently shown how statistical and classical thermodynamics can be employed to evaluate dependencies of function of states of gaseous and solid compounds on temperature and how enthalpies and temperatures of sublimation at standard pressure, as well as vapour pressurevs. temperature dependencies can be predicted.
- Published
- 1995
26. Crystal structure and molecular packing analysis of 1,5-anhydropentitols and per-O-acetyl derivatives
- Author
-
Kosturkiewicz Z, Madaj J, Skorupowa E, Wisniewski A, Pawel Dokurno, and Sokolowski J
- Subjects
Inorganic Chemistry ,Crystallography ,Chemistry ,Stereochemistry ,Cyclohexane conformation ,Theoretical methods ,Molecule ,General Materials Science ,Orthorhombic crystal system ,Crystal structure ,Condensed Matter Physics ,Monoclinic crystal system - Abstract
The crystal structures of three 1,5-anhydropentitols of formulae C5H10O4 and their per-O-acetyl derivatives of formulae C11H16O7 are reported. 1,5-anhydro-D-arabinitol (ADA), 1,5-anhydroribitol (AR), 1,5-anhydroxylitol (AX), 2,3,4-tri-O-acetyl-1,5-anhydro-D-arabinitol (AcADA), 2,3,4-tri-O-acetyl-1,5-anhydroribitol (AcAR) and 2,3,4-tri-O-acetyl-1,5-anhydroxylitol (AcAX) have the following space group and unit cell parameters: ADA, orthorhombic, P212121, a = 6.521(1) Å, b = 6.826(1) Å, c = 13.557(3) Å; AR, monoclinic, P21/n, a = 6.515(1) Å, b = 12.003(1) Å, c = 8.272(1) Å, β = 105.65(1)°; AX, monoclinic, P21/n, a = 6.652(2) Å, b = 9.224(2) Å, c = 10.548(2) Å, β = 101.80(1)°; AcADA, orthorhombic, P212121, a = 8.182(2) Å, = 10.768(2) Å, c = 15.111(3) Å; AcAR, monoclinic, P21/c, a = 15.178(1) Å, b = 10.339(1) Å, c = 8.038(1) Å, β = 92.50(1)°; and AcAX, monoclinic, P21/c, a = 12.092(1) Å, b = 9.066(1) Å, c = 12.492(2) Å, β = 102.39(1)°. The structures were solved using direct methods and refined by full-matrix least-squares techniques to R indices of 0.033, 0.042, 0.045, 0.066, 0.055 and 0.048, respectively. The pyranoid ring adopts 4C1 chair confirmation in the molecules of AR, AX and AcAX, and the 1C4 one in the molecules of ADA, AcADA and AcAR. Theoretical methods were used to examine lattice energetics and molecular packing in the crystals formed.
- Published
- 1995
27. The Synthesis and Structure of Selected Methyl (3,4-Di-O-acetyl-2-deoxy-2-hydroxyimino-<scp>d</scp>-arabino-hexopyranosid)urontes
- Author
-
Pawel Dokurno, Iwona Chrzczanowicz, Zygfryd Smiatacz, and Henryk Myszka
- Subjects
chemistry.chemical_classification ,Ethanol ,Organic Chemistry ,Glycoside ,Pyrazole ,Biochemistry ,Medicinal chemistry ,Chloride ,chemistry.chemical_compound ,chemistry ,Nucleophile ,medicine ,Proton NMR ,medicine.drug - Abstract
Dimeric methyl (3,4-di-O-acetyl-2-deoxy-2-nitroso-α-d-glucopyranosyl chloride)uronate (1) reacts with nucleophiles such as: ethanol, pyrazole, methyl N-tert-butyloxycarbonyl-L-serinate to give corresponding glycosides. The stereospecifity of the glycosidation reaction depends mainly on the employed nucleophile. The configuration and conformation of the obtained glycosides were established on the basis of 1H NMR and polarimetric data, and additionally the structure of 1-(methyl 3,4-di-O-acetyl-2-deoxy-2-(Z)-hydroxyimino-α-d-arabino-hexopyranosyluronate)pyrazole (6), was supported by X-ray diffraction data.
- Published
- 1995
28. Theoretical Studies on the Structure, Thermochemistry, Vibrational Spectroscopy, and Other Features of HfX62- (X = F, Cl, Br, I). Electrostatic Energy in Hexahalogenohafnates
- Author
-
Maciej Gutowski, Jerzy Blazejowksi, Janusz Rak, and Pawel Dokurno
- Subjects
Inorganic Chemistry ,Chemistry ,Electric potential energy ,Thermochemistry ,Physical chemistry ,Infrared spectroscopy ,Physical and Theoretical Chemistry - Published
- 1994
29. Crystal structures of N-aryl-N-pentopyranosylamines
- Author
-
Zygfryd Smiatacz, Henryk Myszka, Jacek Łubkowski, and Pawel Dokurno
- Subjects
Glycosylamine ,medicine.drug_class ,Stereochemistry ,Aryl ,Space group ,Carboxamide ,Crystal structure ,Condensed Matter Physics ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystallography ,Tetragonal crystal system ,chemistry ,medicine ,General Materials Science ,Amine gas treating ,Orthorhombic crystal system - Abstract
The crystal structures of three N-glycosides are reported. The N-p-nitrophenyl-N-(2,3,4-tri-O-acetyl-β-D-lyxopyranosyl)amine (1), N-p-nitrophenyl-N-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)amine (2) and N-acetyl-N-p-nitrophenyl-N-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)amine (3) have the following space groups and unit cell parameters: compound 1 (C17H20N2O9), orthorhombic, P212121 a = 8.004(2) Å, b = 10.603(2) Å, c = 22.695(5) Å; Z = 4 compound 2 (C17H20N2O9)), tetragonal, P43212, a = 9.704(2) Å, c = 41.271(9) Å Z = 8 and compound 3 (C19H22N2O10), orthorhombic, P212121, a = 8.132(2) Å, b = 12.705(2) Å, c = 21.160(4) Å Z = 4. The structures were solved by using direct methods and refined by full-matrix least-squares techniques to R indices of 0.050, 0.041 and 0.067, respectively. These compounds have normal geometry with the 4C1 conformation of the pyranoid ring.
- Published
- 1994
30. Theoretical Studies on the Geometry, Thermochemistry, Vibrational Spectroscopy, and Charge Distribution in TiX62- (X = F, Cl, Br, I). Coulombic Energy in hexahalogenotitanate Lattices
- Author
-
Janusz Rak, Pawel Dokurno, Maciej Gutowski, and Jerzy Błażejowski
- Subjects
Chemistry ,General Engineering ,Thermochemistry ,Vibrational energy relaxation ,Infrared spectroscopy ,Charge density ,Physical and Theoretical Chemistry ,Atomic physics ,Molecular physics ,Energy (signal processing) - Published
- 1994
31. Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity
- Author
-
Nicola Allen, Lindsey Terry, Andrew Massey, Michael Wood, Natalia Matassova, Allan E. Surgenor, Terry Shaw, Martin J. Drysdale, Geraint L. Francis, Yikang Wang, Pawel Dokurno, Christopher John Graham, Rachel Parsons, Rob Howes, Jenifer Borgognoni, Douglas S. Williamson, Zoe Daniels, James Brooke Murray, Macias Alba, and Alexandra Clay
- Subjects
Models, Molecular ,Protein Conformation ,Adenylyl Imidodiphosphate ,Calorimetry ,Crystallography, X-Ray ,Ligands ,chemistry.chemical_compound ,Structure-Activity Relationship ,Adenosine Triphosphate ,Drug Discovery ,Protein A/G ,Protein Isoforms ,HSP70 Heat-Shock Proteins ,Binding site ,Furans ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Adenosine Triphosphatases ,Binding Sites ,biology ,Binding protein ,HSC70 Heat-Shock Proteins ,Isothermal titration calorimetry ,Stereoisomerism ,Surface Plasmon Resonance ,78 kDa Glucose-Regulated Protein ,chemistry ,Biochemistry ,Purines ,Chaperone (protein) ,biology.protein ,Molecular Medicine ,Thermodynamics ,Protein G ,Adenosine triphosphate ,Protein Binding - Abstract
78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM and 14 with K(D) = 60 nM. X-ray crystal structures of Grp78 bound to ATP, ADPnP, and adenosine derivative 10 revealed differences in the binding site between Grp78 and homologous proteins.
- Published
- 2011
32. ChemInform Abstract: Structure of (.+-.)-Egenine
- Author
-
Z. Kosturkiewicz, M. D. Rozwadowska, M. Gdaniec, D. Matecka, and Pawel Dokurno
- Subjects
chemistry.chemical_compound ,Crystallography ,chemistry ,Atom ,Hemiacetal ,Nanotechnology ,General Medicine ,Isoquinoline - Abstract
6,8-Dihydro-6-(5,6,7,8-tetrahydro-6-me thyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl)furo[3,4-e]- 1,3-benzodioxol-8-ol, C 20 H 19 NO 6 , M r =369.4, tri clinic, P1, a=10.833 (2), b=13.184 (3), c=13.375 (3) A, a=89.73 (3), b=74.52 (3), γ=71.95 (3) o , V=1744.0 (5) A 3 , Z=4, D x =1.407 g cm -3 , λ(Cu Kα)=1.54178 A, μ=8.30 cm -1 , F(000)=776, room temperature, R=0.051 for 3375 observed reflections. The relative con figuration of the hemiacetal C atom is established. The heterocyclic fragment of isoquinoline exhibits a half-chair conformation; all five-membered rings show envelope conformations
- Published
- 2010
33. ChemInform Abstract: The Synthesis and Structure of Selected Methyl (3,4-Di-O-acetyl-2- deoxy-2-hydroxyimino-D-arabino-hexopyranosid)uronates
- Author
-
I. Chrzczanowicz, Zygfryd Smiatacz, Henryk Myszka, and Pawel Dokurno
- Subjects
Chemistry ,Stereochemistry ,Nanotechnology ,General Medicine - Published
- 2010
34. ChemInform Abstract: Synthesis, X-Ray Structure and High-Resolution NMR Spectroscopy of Methyl 3-Azido-2,3-dideoxy-α-D-arabino-hexopyranoside (XI)
- Author
-
Pawel Dokurno, Zygfryd Smiatacz, Aleksandra Dabrowska, and Antoni Konitz
- Subjects
Crystallography ,High resolution nmr ,Chemistry ,X-ray ,General Medicine ,Spectroscopy - Published
- 2010
35. Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas
- Author
-
Alan Robertson, Guy A. Kennett, Stephen D. Roughley, Geraint L. Francis, K Benwell, Melanie Wong, Rachel Parsons, A Misra, Timothy Haymes, Hart Terance William, Howard Langh Am Mansell, Macias Alba, Anthony Padfield, Sean Lightowler, Jalanie D’Alessandro, Natalia Matassova, Ben Gibbons, Teresa Brooks, Steven B. Walls, Robert M. Pratt, and Pawel Dokurno
- Subjects
Stereochemistry ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Azetidine ,Pharmaceutical Science ,Ether ,Stereoisomerism ,Biochemistry ,Catalysis ,Amidase ,Amidohydrolases ,chemistry.chemical_compound ,Mice ,Piperidines ,Receptor, Cannabinoid, CB1 ,Fatty acid amide hydrolase ,Drug Discovery ,Animals ,Humans ,Urea ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Mice, Knockout ,biology ,Organic Chemistry ,Rats ,Enzyme ,nervous system ,chemistry ,Models, Chemical ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Azetidines ,lipids (amino acids, peptides, and proteins) ,Selectivity ,psychological phenomena and processes - Abstract
We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1.
- Published
- 2009
36. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design
- Author
-
Douglas S. Williamson, Allan E. Surgenor, Rob Howes, James Brooke Murray, Martin J. Drysdale, Lindsey Terry, Jenifer Borgognoni, Andrew Massey, Michael Wood, Alexandra Clay, Christopher John Graham, Geraint L. Francis, Nicolas Foloppe, Zoe Daniels, Yikang Wang, Rachel Parsons, Pawel Dokurno, Macias Alba, and Terry Shaw
- Subjects
Adenosine ,biology ,Molecular Structure ,Chemistry ,Cell growth ,Crystallography, X-Ray ,Hsp90 ,Hsp70 ,Biochemistry ,Cell culture ,Chaperone (protein) ,Heat shock protein ,Cell Line, Tumor ,Drug Design ,Drug Discovery ,Fluorescence Polarization Immunoassay ,medicine ,biology.protein ,Molecular Medicine ,Humans ,HSP70 Heat-Shock Proteins ,Cytotoxicity ,neoplasms ,medicine.drug - Abstract
The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displayed potency against HCT116 cells. Exposure of compound 12 to HCT116 cells caused significant reduction in cellular levels of Raf-1 and Her2 at concentrations similar to that which caused cell growth arrest.
- Published
- 2009
37. Thermal behaviour and thermochemistry of ethanaminium iodides
- Author
-
Jerzy Błażejowski, Pawel Dokurno, and J. Lubkowski
- Subjects
Thermogravimetry ,Primary decomposition ,Chemistry ,Phase (matter) ,Thermochemistry ,Thermodynamics ,Organic chemistry ,Amine gas treating ,Crystal structure ,Thermal analysis ,Standard enthalpy of formation - Abstract
Dynamic thermoanalytical methods (DTA, TG, DTG) have been applied to the investigation of the thermal features of compounds of general formula (EtnNH4−n)I, withn=0–4. The primary decomposition step of these derivatives is accompanied by the release of amine and HI to the gaseous phase. The enthalpies of this process have been evaluated on the basis of the van't Hoff equation and analytical TG curves. Values thus derived together with the available literature data were used to estimate the enthalpies of formation and the energies of the crystal lattice of the compounds. Further information regarding this latter quantity was also drawn from the Kapustinskii-Yatsimirskii formula.
- Published
- 1990
38. Thermal properties, thermolysis and thermochemistry of alkanaminium iodides
- Author
-
Pawel Dokurno, Jerzy Błȧejowski, and Jacek Łubkowski
- Subjects
chemistry.chemical_classification ,Arrhenius equation ,Thermogravimetric analysis ,Lattice energy ,Iodide ,Thermal decomposition ,Inorganic chemistry ,Thermodynamics ,Crystal structure ,Condensed Matter Physics ,Decomposition ,symbols.namesake ,chemistry ,symbols ,Thermochemistry ,Physical and Theoretical Chemistry ,Instrumentation - Abstract
The thermal features of unbranched compounds of general formula [(CnH2n+1)pNH4−p]I, with n = 0–4 and p =1–4, were studied by thermoanalytical methods (DTA, TG, DTG and Q-TG). All the compounds studied undergo decomposition upon heating, leading to their total volatilisation. In the primary step of the thermal dissociation of these derivatives, HI or RI, in the case of quaternary salts, and the appropriate amines are released in the gaseous phase. This simple thermal decomposition pattern is usually complicated by secondary reactions of an oxidative nature. The latter processes most probably originate from the thermal instability of HI, which can spontaneously decompose to H2 and I2 giving iodine molecules of high oxidative potential. The enthalpies of the thermal dissociation were estimated on the basis of the van't Hoff equation using dynamic thermogravimetric curves. Values derived in this way were used together with available literature data to evaluate the enthalpies of formation and the crystal lattice energies of the hydriodides studied. The crystal lattice energy problems were also examined within the Kapustinskii-Yatsimirskii approach. An attempt was made to describe the kinetics of the thermal decomposition by adopting an Arrhenius model. The influence of the structure of the amines on the thermal behaviour of their iodide salts is reviewed and thoroughly discussed.
- Published
- 1990
39. Conformation of cyclodipeptides. factor analysis: a convenient tool for simplifying conformational studies of condensed poly-ring systems: prolyltype cyclopeptides
- Author
-
Aleksandra S. Kołodziejczyk, Bogdan Liberek, Jerzy Ciarkowski, Pawel Dokurno, M. Gdaniec, and St. Ołdziej
- Subjects
Crystallography ,Chemistry ,Physical and Theoretical Chemistry ,Amino acid residue ,Condensed Matter Physics ,Ring (chemistry) ,Biochemistry ,Conformational isomerism ,Basis set - Abstract
AFA analysis (AFA), also known as principal-component analysis, was used in conformational studies of the condensed 2,5-dioxopiperazine/pyrrolydine (DOP/PYR) 6/5-membered two-ring system, a compound typical of cyclodipeptides comprising prolyl-type amino acid residues. The study is based on the analysis of 30 various X-ray conformers of the molecular frame in question. The results were evaluated and discussed using ring-puckering theory (RPT) as a reference. Complete mutual correspondence between the AFA and the RPT results was found, when both rings are considered separately, which is the prerequisite to using RPT. This correspondence allows a clear-cut physical interpretation of the AFA results, which are otherwise abstract in nature. Thus, two or three independent puckering variables were found for the DOP and PYR rings, respectively, and they acquire the physical significance of the absolute amplitudes of the basic pucker modes, typical of the respective rings. The term absolute is used for puckering with respect to the planar conformer of reference. Subsequent AFA treatment of the condensed DOP/PYR system allowed identification of five conformational variables necessary and sufficient to describe the concerted two-ring puckering completely. Each of the respective basic pucker modes defines a unique pattern of conformational variation of the whole two-ring system. In contrast to the separated ring cases, the origin of the five-dimensional conformational space of DOP/PYR is placed at the mean conformer and it spans physically accessible conformational deviations around the mean. When a conformer other than the mean (e.g. planar) one is chosen initially as a reference, AFA automatically brings the system to the basis set of local deviations around the mean. The results obtained demonstrate that AFA may be a very powerful technique in conformational studies based on an evaluation of a large collection of mutually consistent data. Factor analysis is especially useful in analyses of condensed poly-ring systems, not amenable to the RPT treatment.
- Published
- 1990
40. Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2
- Author
-
Alan Robertson, Justin Bower, Andrew Cansfield, Pawel Dokurno, James B. Murray, Jonathan D. Moore, Jenifer Powles, Geraint L. Francis, Richard Hebdon, Martin J. Parratt, Andrea M. Lockie, Douglas S. Williamson, Philip Stephen Jackson, Allan E. Surgenor, Christopher J. Torrance, Claire L. Nunns, Christine M. Richardson, and Rob Howes
- Subjects
Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Pyrazolopyrimidine ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Cyclin-dependent kinase ,Cell Line, Tumor ,Drug Discovery ,CDC2 Protein Kinase ,CDC2-CDC28 Kinases ,Humans ,Protein kinase A ,Molecular Biology ,Cell Proliferation ,Cyclin-dependent kinase 1 ,biology ,Kinase ,Organic Chemistry ,Cyclin-dependent kinase 2 ,Cyclin-Dependent Kinase 2 ,Pyrimidines ,chemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Signal transduction - Abstract
The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3β and other kinases.
- Published
- 2004
41. Structure of (±)-egenine
- Author
-
Pawel Dokurno, M. D. Rozwadowska, D. Matecka, M. Gdaniec, and Z. Kosturkiewicz
- Subjects
chemistry.chemical_compound ,Crystallography ,chemistry ,Atom ,Molecule ,Hemiacetal ,General Medicine ,Crystal structure ,Isoquinoline ,General Biochemistry, Genetics and Molecular Biology - Abstract
6,8-Dihydro-6-(5,6,7,8-tetrahydro-6-me thyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl)furo[3,4-e]- 1,3-benzodioxol-8-ol, C 20 H 19 NO 6 , M r =369.4, tri clinic, P1, a=10.833 (2), b=13.184 (3), c=13.375 (3) A, a=89.73 (3), b=74.52 (3), γ=71.95 (3) o , V=1744.0 (5) A 3 , Z=4, D x =1.407 g cm -3 , λ(Cu Kα)=1.54178 A, μ=8.30 cm -1 , F(000)=776, room temperature, R=0.051 for 3375 observed reflections. The relative con figuration of the hemiacetal C atom is established. The heterocyclic fragment of isoquinoline exhibits a half-chair conformation; all five-membered rings show envelope conformations
- Published
- 1993
42. Crystal structure of the M-fragment of alpha-catenin: implications for modulation of cell adhesion
- Author
-
Pawel Dokurno, David Barford, Nicholas K. Tonks, and Jing Yang
- Subjects
Models, Molecular ,Repetitive Sequences, Amino Acid ,Protein Conformation ,Molecular Sequence Data ,Alpha catenin ,Antiparallel (biochemistry) ,Crystallography, X-Ray ,General Biochemistry, Genetics and Molecular Biology ,Article ,Protein structure ,Cell Adhesion ,Humans ,Amino Acid Sequence ,Cell adhesion ,Cytoskeleton ,Molecular Biology ,General Immunology and Microbiology ,biology ,Sequence Homology, Amino Acid ,Cadherin ,General Neuroscience ,Vinculin ,Peptide Fragments ,Recombinant Proteins ,Cell biology ,Cytoskeletal Proteins ,Catenin ,biology.protein ,Dimerization ,alpha Catenin - Abstract
The cytoskeletal protein alpha-catenin, which shares structural similarity with vinculin, is required for cadherin-mediated cell adhesion, and functions to modulate cell adhesive strength and to link the cadherins to the actin-based cytoskeleton. Here we describe the crystal structure of a region of alpha-catenin (residues 377-633) termed the M-fragment. The M-fragment is composed of a tandem repeat of two antiparallel four-helix bundles of virtually identical architectures that are related in structure to the dimerization domain of alpha-catenin and the tail region of vinculin. These results suggest that alpha-catenin is composed of repeating antiparallel helical domains. The region of alpha-catenin previously defined as an adhesion modulation domain corresponds to the C-terminal four-helix bundle of the M-fragment, and in the crystal lattice these domains exist as dimers. Evidence for dimerization of the M-fragment of alpha-catenin in solution was detected by chemical cross-linking experiments. The tendency of the adhesion modulation domain to form dimers may explain its biological activity of promoting cell-cell adhesiveness by inducing lateral dimerization of the associated cadherin molecule.
- Published
- 2001
43. Structure of the AAA ATPase p97
- Author
-
Paul A. Bates, Pawel Dokurno, Brent E. Gowen, Anthony Shaw, Hisao Kondo, Marin van Heel, Elena V. Orlova, Xiaodong Zhang, Richard H. Newman, Paul S. Freemont, Michael A. Gorman, John M. Lally, Gordon A. Leonard, and Hemmo Meyer
- Subjects
Models, Molecular ,Saccharomyces cerevisiae Proteins ,ATPase ,Valosin-containing protein ,Archaeal Proteins ,Adenylyl Imidodiphosphate ,Molecular Sequence Data ,Vesicular Transport Proteins ,Crystallography, X-Ray ,Membrane Fusion ,Protein Structure, Secondary ,Fungal Proteins ,Mice ,Protein structure ,Adenosine Triphosphate ,ATP hydrolysis ,Valosin Containing Protein ,Animals ,Amino Acid Sequence ,Pliability ,Molecular Biology ,N-Ethylmaleimide-Sensitive Proteins ,Adenosine Triphosphatases ,Fungal protein ,Binding Sites ,biology ,Cryoelectron Microscopy ,Lipid bilayer fusion ,Nuclear Proteins ,Cell Biology ,AAA proteins ,Peptide Fragments ,Cell biology ,Protein Structure, Tertiary ,Rats ,Adenosine Diphosphate ,biology.protein ,Biophysics ,Carrier Proteins ,Biologie ,Sequence Alignment - Abstract
p97, an abundant hexameric ATPase of the AAA family, is involved in homotypic membrane fusion. It is thought to disassemble SNARE complexes formed during the process of membrane fusion. Here, we report two structures: a crystal structure of the N-terminal and D1 ATPase domains of murine p97 at 2.9 A resolution, and a cryoelectron microscopy structure of full-length rat p97 at 18 A resolution. Together, these structures show that the D1 and D2 hexamers pack in a tail-to-tail arrangement, and that the N domain is flexible. A comparison with NSF D2 (ATP complex) reveals possible conformational changes induced by ATP hydrolysis. Given the D1 and D2 packing arrangement, we propose a ratchet mechanism for p97 during its ATP hydrolysis cycle.
- Published
- 2001
44. Crystallization of the Fab fragment of the tumour-specific antibody PR1A3
- Author
-
Pawel Dokurno, H.A. Band, Paul A. Bates, David Snary, Paul S. Freemont, and John M. Lally
- Subjects
biology ,Magnesium ,chemistry.chemical_element ,General Medicine ,Polyethylene glycol ,law.invention ,chemistry.chemical_compound ,Crystallography ,Carcinoembryonic antigen ,chemistry ,Antigen ,Structural Biology ,law ,biology.protein ,Mother liquor ,Antibody ,Crystallization ,Monoclinic crystal system - Abstract
PR1A3 antibody binds specifically to the tumour-associated cell-surface antigen, carcinoembryonic antigen. Crystals of the Fab fragment of the PR1A3 antibody were obtained by vapour diffusion against mother liquor containing Tris-HC1 buffer, pH 8.6, magnesium chloride and polyethylene glycol 4000 as precipitating agent. Crystals belong to the monoclinic space group P2(1) with cell dimensions a = 42.2, b = 216.7, c = 45.9 A and beta = 95.6 degrees. Two Fab fragments are proesent in the asymmetric unit. Diffracted intensities up to 2.9 A resolution have been measured from frozen crystals.
- Published
- 1997
45. Abstract 2782: Bcl-2 selective antagonists show antitumor activity without dose limiting platelet toxicity
- Author
-
Claire L. Nunns, Francisco Cruzalegui, Starck Jérôme-Benoît, John A. Hickman, Michael Wood, Patrick Casara, Stéphane Depil, James Edward Paul Davidson, Natalia Matassova, Christopher John Graham, Alain Bruno, Pawel Dokurno, Thierry Le Diguarher, Alain Pierre, James Murray, Neil Whitehead, Guillaume De Nanteuil, Olivier Geneste, and Chen I-Jen
- Subjects
Cancer Research ,Programmed cell death ,Pharmacology ,Biology ,Oncology ,Mechanism of action ,Apoptosis ,In vivo ,Cell culture ,Toxicity ,medicine ,Platelet ,medicine.symptom ,IC50 - Abstract
Proteins of the Bcl-2 family are central regulators of programmed cell death. Pro-survival Bcl-2 proteins, such as Bcl-2, Bcl-xL and Mcl-1 are often over-expressed in human tumours and participate in tumour initiation, progression and chemo-resistance. Therefore drugs targeting these pro-survival Bcl-2 proteins represent a promising therapeutic approach for cancer treatment. The most advanced drug targeting this protein family is ABT-263, a potent Bcl-2 and Bcl-xL inhibitor showing anti-tumour efficacy in preclinical models of leukaemia and small cell lung carcinoma. Survival of circulating platelets has been shown to be highly Bcl-xL dependent; consequently the dose-limiting toxicity of ABT-263 is an on-target peripheral thrombocytopenia. We have used a range of biophysical methods to guide the structure-based generation of a significant number of small molecules,* which bind with high affinity (MW < 780; KD < 1 nM) to the BH3 binding groove of Bcl-2, and with high selectivity versus other members of the Bcl-2 family (selectivity > 100 fold). In cellular assays, our lead compounds efficiently displace Bax from Bcl-2 with near complete inhibition of Bcl-2 / Bax co-immunoprecipitation at 100 nM. These compounds are strong inducers of cell death in Bcl-2 dependent cellular models such as the acute myeloblastic leukaemia (AML) cell line RS4;11, affording sub-10 nM IC50's for the most potent compounds. In vivo, in agreement with their mechanism of action, these Bcl-2 selective inhibitors, given either intravenously or orally, elicit a rapid (30 min iv, and 2 hours po) and strong apoptotic response in mouse xenografts of the RS4:11 cell line. When the most potent compounds are given orally to RS4;11 xenograft-bearing mice, apoptosis in tumor cells is induced more than 15 fold (at 25 mg/kg) and more than 20 fold (at 50 mg/kg) compared to untreated mice. Importantly, in agreement with the selectivity of the compounds for Bcl-2 versus Bcl-xL, no platelet loss was observed in mice treated with our compounds, in sharp contrast to ABT-263. Finally, we observe very robust anti-tumor activity when a lead compound is given orally at 50 mg/kg and 100 mg/kg (with complete regression at 100 mg/kg) in an RS4;11 mouse xenograft model. This anti-tumor activity was similar whether the compound was dosed daily or twice a week over two weeks. Altogether our data demonstrate that highly Bcl-2 selective antagonists show anti-tumor activity and no platelet toxicity, in contrast to Bcl-2 / Bcl-xL dual inhibitors. Such compounds represent promising drug candidates for the treatment of Bcl-2 dependent malignancies such as chronic lymphocytic leukaemia (CLL) and other leukaemias and lymphomas. * Chemical structures of compounds will not be disclosed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2782. doi:1538-7445.AM2012-2782
- Published
- 2012
46. Corrigendum to 'Structure-guided design of α-amino acid-derived Pin1 inhibitors' [Bioorg. Med. Chem. Lett. 20 (2010) 586]
- Author
-
Claire L. Nunns, Jonathan D. Moore, Simon F. Scrace, David A. Robinson, Lisa Baker, Pawel Dokurno, James Brooke Murray, Natalia Matassova, Louisa Gueritz, Andrew J. Potter, Stuart C. Ray, Christine M. Richardson, Ben Davis, Christopher J. Bryant, and Allan E. Surgenor
- Subjects
chemistry.chemical_classification ,chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,PIN1 ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry ,Amino acid - Published
- 2010
47. Abstract A212: A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor-induced apoptosis in HCT116 colon carcinoma cells
- Author
-
Andrew Massey, Michael Wood, Rachel Parsons, Pawel Dokurno, Yikang Wang, Zoe Daniels, Christopher John Graham, Terry Shaw, Macias Alba, Jennifer Borgognoni, Geraint L. Francis, Natalia Matassova, Douglas S. Williamson, Helen Browne, Martin J. Drysdale, and James Brooke Murray
- Subjects
Cancer Research ,Programmed cell death ,Oncology ,Apoptosis ,Cell growth ,biology.protein ,Cell cycle ,Biology ,Protein degradation ,Hsp90 ,Small molecule ,Hsp90 inhibitor ,Cell biology - Abstract
The role of the 70 kDa heat shock protein isoforms (Hsc70 and Hsp70) in cancer development and progression through their ability to inhibit apoptosis and via their role as Hsp90 co-chaperones has been well documented. Dual targeting of Hsc70 and Hsp70 with siRNA has previously been demonstrated to induce proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. The design and synthesis of novel adenosine-derived inhibitors of Hsp70, guided by modelling and X-ray crystallographic structures of these compounds in complex with Hsc70/BAG-1, has been described.1 These were the first inhibitors described to target the ATPase binding domain of this family of chaperones. Many of these compounds exhibited submicromolar affinity for Hsp70, were highly selective over Hsp90, and displayed in vitro activity against a variety of human tumor cell lines. We further describe the in vitro mode of action of one of the most potent analogues, VER-155008 in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell cycle, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI50s in the range 5.3 to 14.4 M, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 and HT29 cells. VER-155008 potentiated the apoptotic potential of the small molecule Hsp90 inhibitors VER-821602 and 17-AAG in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. These data suggest that as a single agent, small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A212.
- Published
- 2009
48. Electrostatic Energy in Inorganic and Organic Salts Containing Octahedral SnCl62- Ion
- Author
-
J. Lubkowski, Jerzy Błażejowski, J Czerminski, and Pawel Dokurno
- Subjects
Lattice energy ,Chemistry ,Charge density ,Physical chemistry ,Ionic bonding ,MNDO ,Density functional theory ,General Chemistry ,Crystal structure ,Alkali metal ,Ion - Abstract
Hexachlorostannic acid is a precursor of derivatives of an ionic nature. The electrostatic part of the lattice energy in alkali metal salts and nitrogen organic base salts containing the SnCl62- ion was determined by adopting the Ewald method. This approach requires knowledge of the complete or at least partial crystal structures of the compounds. In the case of incomplete structures the MNDO geometry optimization procedure was successfully applied to find the unknown positions of atoms, and thus permitted a wider representation of compounds to be considered. The crystal lattice energy calculations were carried out by taking from four different literature sources data regarding charge distribution in SnCl62-. It was further assumed that the positive charge in cations was located either directly on certain atoms or distributed between all the atoms in these ions. These latter net atomic charges were evaluated by applying INDO and MNDO methods. The electrostatic energies derived compare well with published values of the crystal lattice energy; this implies that, in the case of the compounds examined, the main contribution to the cohesive forces is made by Coulombic interactions.
- Published
- 1991
49. Crystal structure and lattice energetics of 10-methylacridinium halides
- Author
-
Pawel Dokurno, Piotr Storoniak, Antoni Konitz, Karol Krzymiński, and Jerzy Błażejowski
- Subjects
Lattice energy ,Hydrogen bond ,Chemistry ,Intermolecular force ,Supramolecular chemistry ,General Chemistry ,Crystal structure ,Triclinic crystal system ,Crystallography ,symbols.namesake ,symbols ,Physical chemistry ,Molecule ,van der Waals force - Abstract
The crystal structures of 10-methylacridinium chloride monohydrate, bromide monohydrate and iodide were determined by X-ray analysis. The compounds crystallize in the triclinic space group, P¯1, with 2 molecules in the unit cell. The molecular arrangement in the crystals revealed that hydrogen bonds (in hydrates) and van der Waals contacts play a significant part in intermolecular interactions. To discover their nature, contributions to the crystal lattice energy arising from electrostatic (the most important since the compounds form ionic crystals), dispersive and repulsive interactions were calculated. Enthalpies of formation of the salts, their stability and susceptibility to decomposition could be predicted from a combination of crystal lattice energies with values of other thermochemical characteristics obtained theoretically or taken from the literature. The role of water in the stabilization of the crystal lattice of the hydrates is also explained. The information gathered has given an insight into the features and behaviour of compounds which can be regarded as models of a large group of aromatic quaternary nitrogen salts.
50. Crystal lattice energy of aminoacid hydrohalides
- Author
-
Jerzy Błażejowski, Piotr Skurski, Jacek Rulewski, and Pawel Dokurno
- Subjects
Lattice energy ,Chemistry ,Intermolecular force ,Ab initio ,Condensed Matter Physics ,Electrostatics ,Partial charge ,Chemical physics ,Atom ,Physics::Atomic and Molecular Clusters ,Physical chemistry ,Density functional theory ,Physics::Chemical Physics ,Mulliken population analysis - Abstract
Basic relationships concerning thermodynamics of crystalline phases and the process of their formation, as well as energetics of intermolecular interactions in these, were invoked and discussed from the point of view of their application in studies of stability, features and behaviour of solid systems. Further, electrostatic, dispersive and repulsive contributions to the crystal lattice energy of 25 hydrohalides of aminoacids were calculated assuming that each atom of the basic stoichiometric unit interacts with all atoms from surroundings. Energy of electrostatic interactions was obtained assuming 1+ and 1 -charges on cation and anion, respectively, and using atomic partial charges resulting from Mulliken population analysis or fitted so as to reproduce molecular electrostatic potential (MEP) around molecules, determined on ab initio Hartree-Fock (HF) or density functional theory (DFT) levels. Dispersive and repulsive contributions were evaluated by either Lennard-Jones or Buckingham equations u...
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