28 results on '"Douglas S. Williamson"'
Search Results
2. 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
- Author
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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
- Subjects
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.
- Published
- 2021
3. 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
- Published
- 2021
4. 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...
- Published
- 2017
5. Selective LRRK2 kinase inhibition reduces phosphorylation of endogenous Rab10 and Rab12 in human peripheral mononuclear blood cells
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Karina Fog, Felix S. Oppermann, Kenneth Vielsted Christensen, Kenneth Thirstrup, Justus C. Dächsel, Garrick Paul Smith, and Douglas S. Williamson
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0301 basic medicine ,Proteomics ,Proteome ,lcsh:Medicine ,Pharmacology ,Biology ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Peripheral blood mononuclear cell ,Article ,Immunomodulation ,03 medical and health sciences ,Humans ,Kinase activity ,Phosphorylation ,lcsh:Science ,IC50 ,Protein Kinase Inhibitors ,Multidisciplinary ,Dose-Response Relationship, Drug ,Kinase ,HEK 293 cells ,lcsh:R ,Phosphoproteomics ,Computational Biology ,Reproducibility of Results ,Phosphoproteins ,LRRK2 ,nervous system diseases ,030104 developmental biology ,rab GTP-Binding Proteins ,Immunology ,Leukocytes, Mononuclear ,lcsh:Q - Abstract
Genetic variation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with risk of familial and sporadic Parkinson’s disease (PD). To support clinical development of LRRK2 inhibitors as disease-modifying treatment in PD biomarkers for kinase activity, target engagement and kinase inhibition are prerequisite tools. In a combined proteomics and phosphoproteomics study on human peripheral mononuclear blood cells (PBMCs) treated with the LRRK2 inhibitor Lu AF58786 a number of putative biomarkers were identified. Among the phospho-site hits were known LRRK2 sites as well as two phospho-sites on human Rab10 and Rab12. LRRK2 dependent phosphorylation of human Rab10 and human Rab12 at positions Thr73 and Ser106, respectively, was confirmed in HEK293 and, more importantly, Rab10-pThr73 inhibition was validated in immune stimulated human PBMCs using two distinct LRRK2 inhibitors. In addition, in non-stimulated human PBMCs acute inhibition of LRRK2 with two distinct LRRK2 inhibitor compounds reduced Rab10-Thr73 phosphorylation in a concentration-dependent manner with apparent IC50’s equivalent to IC50’s on LRRK2-pSer935. The identification of Rab10 phosphorylated at Thr73 as a LRRK2 inhibition marker in human PBMCs strongly support inclusion of assays quantifying Rab10-pThr73 levels in upcoming clinical trials evaluating LRRK2 kinase inhibition as a disease-modifying treatment principle in PD.
- Published
- 2017
6. 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.
- Published
- 2019
7. Recent Progress in Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors for the Treatment of Parkinson's Disease
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Douglas S. Williamson, Kenneth Vielsted Christensen, and Morten Jørgensen
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Parkinson's disease ,Kinase ,medicine ,Pharmacology ,Leucine-rich repeat ,Biology ,medicine.disease ,LRRK2 - Published
- 2018
8. The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors
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Laurent David, Garrick Paul Smith, Victoria Chell, Lassina Badolo, Stephen P. Watson, Douglas S. Williamson, Morten Hentzer, Chen I-Jen, Gitte Mikkelsen, Martin C. Herzig, Kenneth Vielsted Christensen, and Justus Claus Alfred Daechsel
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Clinical Biochemistry ,Pharmaceutical Science ,Aminopyridines ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,01 natural sciences ,Biochemistry ,Mixed Lineage Kinase ,Madin Darby Canine Kidney Cells ,chemistry.chemical_compound ,Structure-Activity Relationship ,Dogs ,In vivo ,Drug Discovery ,Animals ,Humans ,Homology modeling ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Kinase ,Organic Chemistry ,LRRK2 ,nervous system diseases ,0104 chemical sciences ,Rats ,010404 medicinal & biomolecular chemistry ,chemistry ,Drug Design ,Microsomes, Liver ,Molecular Medicine ,2-Aminopyridine - Abstract
Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.
- Published
- 2017
9. Development of LRRK2 Inhibitors for the Treatment of Parkinson's Disease
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Garrick Paul Smith, Kenneth Vielsted Christensen, and Douglas S. Williamson
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0301 basic medicine ,Genetics ,Parkinson's disease ,Locus (genetics) ,Biology ,medicine.disease ,LRRK2 ,Homology (biology) ,In vitro ,nervous system diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Structural biology ,medicine ,Homology modeling ,030217 neurology & neurosurgery ,Genetic association - Abstract
Linkage and genome-wide association studies have identified a genetic risk locus for late-onset Parkinson's disease in chromosome 12, originally identified as PARK6. The causative gene was identified to code for a large multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment. Although LRRK2 has so far not been crystallised, the use of homology modelling and crystallographic surrogates has allowed the optimisation of chemical structures such that compounds of high selectivity with good brain penetration and appropriate pharmacokinetic properties are now available for understanding the biology of LRRK2 in vitro and in vivo. This chapter reviews LRRK2 biology, the structural biology of LRRK2 and gives an overview of inhibitors of LRRK2.
- Published
- 2017
10. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells
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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
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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
11. Antagonists of the human adenosine A2A receptor. Part 3: Design and synthesis of pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines and 6-arylpurines
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A Misra, Jonathan Richard Anthon Roffey, Colin T. Dourish, Joanne Lerpiniere, Rebecca Upton, Roger John Gillespie, Claire Elizabeth Dawson, Suneel Gaur, Scott Murray Weiss, Douglas S. Williamson, Robert M. Pratt, Gemma Caroline Stratton, Ian Anthony Cliffe, Allan M. Jordan, and Antony R. Knight
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Purine ,Pyrimidine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Adenosine A2A receptor ,Adenosine A1 Receptor Antagonists ,Biochemistry ,Chemical synthesis ,Antiparkinson Agents ,Structure-Activity Relationship ,chemistry.chemical_compound ,Parkinsonian Disorders ,In vivo ,Drug Discovery ,Humans ,Structure–activity relationship ,Receptor ,Molecular Biology ,Bicyclic molecule ,Organic Chemistry ,Stereoisomerism ,Adenosine A2 Receptor Antagonists ,Pyrimidines ,Models, Chemical ,chemistry ,Purines ,Drug Design ,Pyrazoles ,Molecular Medicine - Abstract
A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A(2A) antagonists is described. Many examples were highly selective against the human A(1) receptor sub-type and were active in an in vivo model of Parkinson's disease.
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- 2008
12. Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives
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David R. Adams, Suneel Gaur, Simon E. Ward, A Misra, Allan Fletcher, Claire Elizabeth Dawson, Porter Richard Hugh Phillip, Anthony Lawrence, P R Giles, Ian Anthony Cliffe, Lars J. S. Knutsen, Colin T. Dourish, Scott Murray Weiss, Roger John Gillespie, Antony R. Knight, Allan M. Jordan, Robert M. Pratt, K Benwell, Douglas S. Williamson, Joanne Lerpiniere, Robin Shepherd, David Bebbington, and Rebecca Upton
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Drug ,Pyrimidine ,Stereochemistry ,medicine.drug_class ,media_common.quotation_subject ,Clinical Biochemistry ,Pharmaceutical Science ,Adenosine A2A receptor ,Biochemistry ,Antiparkinson Agents ,Antimalarials ,Structure-Activity Relationship ,chemistry.chemical_compound ,Parkinsonian Disorders ,In vivo ,Drug Discovery ,medicine ,Humans ,Receptor ,Molecular Biology ,media_common ,Chemistry ,Mefloquine ,Organic Chemistry ,Stereoisomerism ,Receptor antagonist ,Adenosine A2 Receptor Antagonists ,Pyrimidines ,Models, Chemical ,Molecular Medicine ,Selectivity ,medicine.drug - Abstract
The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.
- Published
- 2008
13. Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping
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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
14. Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: Protein structure-guided design and SAR
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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
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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
15. The synthesis of 4-arylsulfanyl-substituted kainoid analogues from trans-4-hydroxy-l-proline
- Author
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Jack E. Baldwin, Gareth J. Pritchard, and Douglas S. Williamson
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chemistry.chemical_classification ,Kainic Acid ,Stereochemistry ,Chemistry ,Mesylate ,Clinical Biochemistry ,Organic Chemistry ,Pharmaceutical Science ,Chemical synthesis ,Biochemistry ,Amino acid ,Hydroxyproline ,chemistry.chemical_compound ,Sulfonate ,Receptors, Kainic Acid ,Drug Discovery ,Molecular Medicine ,Proline ,Trans-4-Hydroxy-L-proline ,Molecular Biology - Abstract
The potent neuroexcitatory activity of kainoid amino acids in the mammalian CNS places new analogues in high demand as tools for neuropharmacological research. A range of 4-arylsulfanyl-substituted kainoids has been synthesised in a parallel fashion via mesylate displacement by a number of aromatic and heteroaromatic thiolates upon (2S,3S,4R)-1-benzoyl-3-tert-butoxycarbonylmethyl-4-methanesulfonyloxy pyrrolidine-2-carboxylic acid methyl ester 8, which is obtainable in eight steps from trans-4-hydroxy- l -proline 5.
- Published
- 2001
16. Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity
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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
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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
17. Might anabolic steroid abuse provide a defence in cases of violent crime?
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Douglas S. Williamson and Martin Humphreys
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medicine.medical_specialty ,Anabolism ,Aggression ,medicine.medical_treatment ,social sciences ,Criminology ,Violent crime ,Pathology and Forensic Medicine ,Psychiatry and Mental health ,mental disorders ,medicine ,medicine.symptom ,Psychiatry ,Psychology ,human activities ,health care economics and organizations ,Anabolic steroid - Abstract
Anabolic steroid abuse is now widespread both in sport and outside the competitive arena. Psychiatrists may be asked to give an opinion in cases of violent crime involving anabolic steroid abusers. Literature suggesting that anabolic steroids can cause aggressive behaviour, or precipitate mental disorder, is reviewed. The possibility that aggression or mental disorder supposedly due to anabolic steroid abuse might provide a defence in cases of violent crime is discussed.
- Published
- 1993
18. ChemInform Abstract: Practical Radical Cyclizations Leading to the Construction of Near-Stereopure Quaternary Carbon Stereogenic Centres
- Author
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Douglas S. Williamson, Robin G. Pritchard, Richard J. Stoodley, and Raymond McCague
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Chemistry ,Organic chemistry ,General Medicine ,Quaternary carbon ,Stereocenter - Published
- 2010
19. ChemInform Abstract: Synthesis of 4-Arylsulfanyl-Substituted Kainoid Analogues from trans-4-Hydroxy-L-proline
- Author
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Jack E. Baldwin, Douglas S. Williamson, and Gareth J. Pritchard
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chemistry.chemical_classification ,chemistry ,Stereochemistry ,Organic chemistry ,General Medicine ,Trans-4-Hydroxy-L-proline ,Amino acid - Published
- 2010
20. Antagonists of the human A(2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides
- Author
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Alexandra Clay, Philip Stephen Jackson, Heather Simmonite, Howard Langh Am Mansell, Richard S. Todd, Ian Yule, Samantha J Bamford, Mona Saadi, Tim Haymes, Stefania Leonardi, Burlchard Klenke, Douglas S. Williamson, Gemma Caroline Stratton, Allan M. Jordan, Jeanette Liu, Suneel Gaur, Roger John Gillespie, and Sean Ng
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Parkinson's disease ,Movement disorders ,Pyrimidine ,Receptor, Adenosine A2A ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Disease ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,Receptor ,Molecular Biology ,Chemistry ,Organic Chemistry ,Parkinson Disease ,medicine.disease ,Adenosine receptor ,Adenosine A2 Receptor Antagonists ,Pyrimidines ,Molecular Medicine ,medicine.symptom ,Locomotion ,Protein Binding - Abstract
Antagonists of the human A2A receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson’s disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure–activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson’s disease.
- Published
- 2009
21. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design
- Author
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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
22. Transient treatment with CDK inhibitors eliminates proliferative potential even when their abilities to evoke apoptosis and DNA damage are blocked
- Author
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Sarah Denny, Andrew Cansfield, Philip Stephen Jackson, Jonathan D. Moore, Douglas S. Williamson, Peter Kierstan, Lan-Zhen Wang, Simon F. Scrace, Joanne Wayne, Andrea M. Lockie, Nicola J. Curtin, Carol Bentley, David R. Newell, and Jenifer Borgognoni
- Subjects
Programmed cell death ,DNA damage ,Antineoplastic Agents ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Biology ,Cyclin-dependent kinase ,Cell Line, Tumor ,Humans ,CHEK1 ,RNA, Small Interfering ,Molecular Biology ,Oxazoles ,Protein Kinase Inhibitors ,Cell Proliferation ,Cell growth ,Cell Biology ,Cyclin-Dependent Kinases ,XIAP ,Cell biology ,Thiazoles ,Pyrimidines ,Proto-Oncogene Proteins c-bcl-2 ,Cancer cell ,Checkpoint Kinase 1 ,biology.protein ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Pyrazoles ,biological phenomena, cell phenomena, and immunity ,Restriction point ,Protein Kinases ,Developmental Biology ,DNA Damage - Abstract
Transient treatment with small molecule CDK inhibitors is toxic to cancer cells and leads to depletion of anti-apoptotic proteins and Chk1, coupled with DNA damage and induction of apoptosis. Here we have examined, which of these phenomena are necessary for CDK inhibitors to have an anti-proliferative effect. We find that 24 hours treatment with either a primarily CDK2-specific, or a primarily CDK7/9-specific, antagonist eliminates proliferative potential even if apoptosis is blocked and the tendency of CDK inhibition to result in DNA damage is overcome by expression of recombinant Chk1. Loss of proliferative potential is correlated with irreversible suppression of biomarkers of cell cycle progression. CDK inhibitors dramatically reduced levels of the anti-apoptotic proteins, Mcl-1 and XIAP, but siRNA-mediated suppression of Mcl-1 and XIAP did not induce cell death in the osteosarcoma cells used in this study. Finally, we found that many literature CDK inhibitors do not effectively suppress the CDK/cyclin complexes responsible for cell cycle progression at the minimum doses required to block proliferation: some are only effective after a substantial delay and may act via inhibition of CDK7.
- Published
- 2008
23. Antagonists of the human adenosine A2A receptor. Part 2: Design and synthesis of 4-arylthieno[3,2-d]pyrimidine derivatives
- Author
-
Anthony Lawrence, Robert M. Pratt, Richard S. Todd, Joanne Lerpiniere, Antony R. Knight, Ian Anthony Cliffe, Rebecca Upton, Suneel Gaur, Scott Murray Weiss, Claire Elizabeth Dawson, Colin T. Dourish, P R Giles, Roger John Gillespie, A Misra, Allan M. Jordan, and Douglas S. Williamson
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Adenosine A2A receptor ,Adenosine A3 Receptor Antagonists ,Pharmacology ,Adenosine A1 Receptor Antagonists ,Biochemistry ,Antiparkinson Agents ,Structure-Activity Relationship ,Parkinsonian Disorders ,In vivo ,Drug Discovery ,Humans ,Receptor ,Molecular Biology ,Chemistry ,Organic Chemistry ,Stereoisomerism ,Adenosine A3 receptor ,Adenosine receptor ,Adenosine A2 Receptor Antagonists ,Pyrimidines ,Models, Chemical ,Drug Design ,Molecular Medicine ,Adenosine A2B receptor - Abstract
We describe herein the discovery and development of a series of 4-arylthieno(3,2-d)pyrimidines which are potent adeno- sine A2A receptor antagonists. These novel compounds show high degrees of selectivity against the human A1 ,A 2B and A3 receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease. 2008 Elsevier Ltd. All rights reserved. Adenosine receptors comprise four distinct sub-types, designated A1 ,A 2A ,A 2B and A3. In the brain, adenosine A2A receptors are located primarily in the striatum, playing a key role in regulating movement. There is strong evidence that adenosine A2A receptor antagonists may provide a novel therapy for the treatment of Par- kinson's disease, with a lower risk of dyskinesias. 1
- Published
- 2008
24. Identification of non-furan containing A2A antagonists using database mining and molecular similarity approaches
- Author
-
Daniel M. Sellwood, Douglas S. Williamson, Allan M. Jordan, Roger John Gillespie, A Misra, Christine M. Richardson, Alexandra Fink, and Antony R. Knight
- Subjects
Models, Molecular ,Receptor, Adenosine A2A ,Clinical Biochemistry ,Pharmaceutical Science ,computer.software_genre ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Similarity (network science) ,Furan ,Drug Discovery ,Structure–activity relationship ,Moiety ,Furans ,Molecular Biology ,Amination ,Database ,Molecular Structure ,Chemistry ,Organic Chemistry ,Fluorine ,Adenosine A2 Receptor Antagonists ,Pyrimidines ,Molecular Medicine ,Identification (biology) ,Pharmacophore ,Selectivity ,computer ,Protein Binding - Abstract
Database searching led to the identification of potent A 2A antagonists which do not contain the privileged furan moiety and which show selectivity over A 1 receptors. Simple substructure searching on a proprietary database identified compounds with activities in the low nM range. A targeted approach to the identification of non-furan containing compounds resulted in the identification of two novel series, with potency, selectivity and directional SAR from screening 113 compounds.
- Published
- 2006
25. 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
26. ChemInform Abstract: The Synthesis of 4-Arylsulfanyl-Substituted Kainoid Analogues from trans-4-Hydroxy-L-proline
- Author
-
Jack E. Baldwin, Gareth J. Pritchard, and Douglas S. Williamson
- Subjects
General Medicine - Published
- 2000
27. 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
28. Practical radical cyclisations leading to the construction of near-stereopure quaternary carbon stereogenic centres
- Author
-
Richard J. Stoodley, Raymond McCague, Douglas S. Williamson, and Robin G. Pritchard
- Subjects
Chemistry ,Hypophosphite ,Metals and Alloys ,General Chemistry ,Medicinal chemistry ,Catalysis ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Adduct ,Stereocenter ,chemistry.chemical_compound ,Materials Chemistry ,Ceramics and Composites ,Organic chemistry ,Stereoselectivity ,Quaternary carbon - Abstract
The 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl auxiliary is effective in directing bromopropargyloxy additions to the olefinic bonds of vinylogous esters/carbonates; in the presence of AIBN and 1-ethylpiperidinium hypophosphite, the adducts undergo highly stereoselective reductive radical cyclisations in which quaternary carbon stereogenic centres are generated.
- Published
- 1998
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