20 results on '"Newitt, John A."'
Search Results
2. The E. coli signal recognition particle is required for the insertion of the subset of inner...
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Ulbrandt, Nancy D. and Newitt, John A.
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ESCHERICHIA coli - Abstract
Describes the use of a novel genetic approach to elucidate the function of an essential signal recognition particle (SRP)-like particle in E. coli. Gene identification through genome-wide screen; Inhibition of the SRP pathway; Utilization of SRP-independent targeting pathway by E. coli preproteins and inner membrane proteins.
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- 1997
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3. The N-domain of the signal recognition particle 54-kDa subunit promotes efficient signal sequence binding.
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Newitt, John A. and Bernstein, Harris D.
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NUCLEOPROTEINS , *RIBOSOMES , *RIBOSOME structure , *MOLECULAR structure , *GUANOSINE triphosphate , *ENDOPLASMIC reticulum , *ORGANELLES - Abstract
The signal recognition particle 54-kDa subunit (SRP54) binds to the signal sequences of nascent presecretory and transmembrane proteins. Previous studies have shown that signal sequences bind to the C-terminal methionine-rich domain of the protein (M-domain), but have raised the possibility that either the N-terminal domain (N-domain) or the central guanosine triphosphatase module (GTPase-domain) also contribute to signal-sequence-binding activity. We have generated a series of N-domain and GTPase-domain mutants to investigate this issue further. Mutations in a conserved N-domain motif (ALLEADV) produced significant defects in signal sequence binding that correlate with the severity of the mutation. The magnitude of the defect was independent of the preprotein substrate, which suggested that the mutations do not alter the specificity of signal sequence recognition. The N-domain mutants also showed defects in promoting the translocation of presecretory proteins across the membrane of microsomal vesicles, but these defects appeared to be a direct consequence of the reduction in signal-sequence-binding activity and not separate effects of the mutations. By contrast, mutations in the guanosine triphosphatase consensus sequence had no effect on signal sequence binding, but instead severely impaired protein translocation activity. These results indicate that a principal function of the SRP54 N-domain is to promote efficient signal sequence binding. These data also suggest that the SRP54 GTPase regulates the cycle of signal sequence binding and release, perhaps by modulating the relative orientation of the N- and M- domains. [ABSTRACT FROM AUTHOR]
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- 1997
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4. Assessing compound binding to the Eg5 motor domain using a thermal shift assay
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McDonnell, Patricia A., Yanchunas, Joseph, Newitt, John A., Tao, Li, Kiefer, Susan E., Ortega, Marie, Kut, Stephanie, Burford, Neil, Goldfarb, Valentina, Duke, Gerald J., Shen, Henry, Metzler, William, Doyle, Michael, Chen, Zhong, Tarby, Christine, Borzilleri, Robert, Vaccaro, Wayne, Gottardis, Marco, Lu, Songfeng, and Crews, Donald
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KINESIN , *CANCER chemotherapy , *CELL cycle regulation , *MICROTUBULES , *CIRCULAR dichroism , *CALORIMETRY , *TARGETED drug delivery , *SPINDLE apparatus , *VOLUMETRIC analysis - Abstract
Abstract: Eg5 is a kinesin whose inhibition leads to cycle arrest during mitosis, making it a potential therapeutic target in cancers. Circular dichroism and isothermal titration calorimetry of our pyrrolotriazine-4-one series of inhibitors with Eg5 motor domain revealed enhanced binding in the presence of adenosine 5′-diphosphate (ADP). Using this information, we studied the interaction of this series with ADP–Eg5 complexes using a thermal shift assay. We measured up to a 7°C increase in the thermal melting (T m) of Eg5 for an inhibitor that produced IC50 values of 60 and 130nM in microtubule-dependent adenosine triphosphatase (ATPase) and cell-based cytotoxicity assays, respectively. In general, the inhibitor potency of the pyrrolotriazine-4-one series in in vitro biological assays correlated with the magnitude of the thermal stability enhancement of ADP–Eg5. The thermal shift assay also confirmed direct binding of Eg5 inhibitors identified in a high-throughput screen and demonstrated that the thermal shift assay is applicable to a range of chemotypes and can be useful in evaluating both potent (nM) and relatively weakly binding (μM) leads. Overall, the thermal shift assay was found to be an excellent biophysical method for evaluating direct binding of a large number of compounds to Eg5, and it complemented the catalytic assay screens by providing an alternative determination of inhibitor potency. [Copyright &y& Elsevier]
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- 2009
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5. Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1).
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Lau, Wai L., Pearce, Bradley, Malakian, Heather, Rodrigo, Iyoncy, Xie, Dianlin, Gao, Mian, Marsilio, Frank, Chang, Chiehying, Ruzanov, Max, Muckelbauer, Jodi K., Newitt, John A., Lipovšek, Daša, and Sheriff, Steven
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YEAST , *PROTEIN engineering , *DRUG design , *TARGETED drug delivery , *IMMUNE response - Abstract
Hematopoietic progenitor kinase 1 (HPK1) is an intracellular kinase that plays an important role in modulating tumor immune response and thus is an attractive target for drug discovery. Crystallization of the wild‐type HPK1 kinase domain has been hampered by poor expression in recombinant systems and poor solubility. In this study, yeast surface display was applied to a library of HPK1 kinase‐domain variants in order to select variants with an improved expression level and solubility. The HPK1 variant with the most improved properties contained two mutations, crystallized readily in complex with several small‐molecule inhibitors and provided valuable insight to guide structure‐based drug design. This work exemplifies the benefit of yeast surface display towards engineering crystallizable proteins and thus enabling structure‐based drug discovery. [ABSTRACT FROM AUTHOR]
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- 2021
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6. Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1.
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Markwalder, Jay A., Balog, Aaron J., Williams, David K., Nara, Susheel J., Reddy, Ratnakar, Roy, Saumya, Kanyaboina, Yadagiri, Li, Xin, Johnston, Kathy, Fan, Yi, Lewis, Hal, Marsilio, Frank, Yan, Chunhong, Critton, David, Newitt, John A., Traeger, Sarah C., Wu, Dauh-Rurng, Jure-Kunkel, Maria N., Jayaraman, Lata, and Lin, Tai-An
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BIOSYNTHESIS , *ALKYL ethers , *PREGNANE X receptor , *INDOLEAMINE 2,3-dioxygenase , *ION channels , *POTASSIUM channels - Abstract
[Display omitted] Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC 50 = 7.0 nM), an iterative process of synthesis and screening led to cyclized analog 21 (IDO1 HeLa IC 50 = 3.6 nM) which maintained the high potency of 3 while addressing issues of lipophilicity, cytochrome P450 (CYP) inhibition, hERG (human potassium ion channel Kv11.1) inhibition, Pregnane X Receptor (PXR) transactivation, and oxidative metabolic stability. An x-ray crystal structure of a biaryl alkyl ether 11 bound to IDO1 was obtained. Consistent with our earlier results, compound 11 was shown to bind to the apo form of the enzyme. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form.
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Nelp, Micah T., Kates, Patrick A., Hunt, John T., Newitt, John A., Balog, Aaron, Maley, Derrick, Xiao Zhu, Abell, Lynn, Allentoff, Alban, Borzilleri, Robert, Lewis, Hal A., Zeyu Lin, Seitz, Steven P., Chunhong Yan, and Groves, John T.
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IMMUNOREGULATION , *INDOLEAMINE 2,3-dioxygenase , *IMMUNOSUPPRESSION , *KYNURENINE , *T cells , *PHYSIOLOGY - Abstract
For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation. [ABSTRACT FROM AUTHOR]
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- 2018
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8. The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer.
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Padmakar Darne, Chetan, Velaparthi, Upender, Saulnier, Mark, Frennesson, David, Liu, Peiying, Huang, Audris, Tokarski, John, Fura, Aberra, Spires, Thomas, Newitt, John, Spires, Vanessa M., Obermeier, Mary T., Elzinga, Paul A., Gottardis, Marco M., Jayaraman, Lata, Vite, Gregory D., and Balog, Aaron
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CASTRATION-resistant prostate cancer , *SMALL molecules , *ABIRATERONE acetate - Abstract
[Display omitted] We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity.
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Tebben, Andrew J., Ruzanov, Maxim, Gao, Mian, Xie, Dianlin, Kiefer, Susan E., Yan, Chunhong, Newitt, John A., Zhang, Liping, Kim, Kyoung, Lu, Hao, Kopcho, Lisa M., and Sheriff, Steven
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TRANSFORMING growth factors-beta , *CRYSTAL structure , *MEMBRANE proteins - Abstract
The cytokine TGF-β modulates a number of cellular activities and plays a critical role in development, hemostasis and physiology, as well as in diseases including cancer and fibrosis. TGF-β signals through two transmembrane serine/threonine kinase receptors: TGFβR1 and TGFβR2. Multiple structures of the TGFβR1 kinase domain are known, but the structure of TGFβR2 remains unreported. Wild-type TGFβR2 kinase domain was refractory to crystallization, leading to the design of two mutated constructs: firstly, a TGFβR1 chimeric protein with seven ATP-site residues mutated to their counterparts in TGFβR2, and secondly, a reduction of surface entropy through mutation of six charged residues on the surface of the TGFβR2 kinase domain to alanines. These yielded apo and inhibitor-bound crystals that diffracted to high resolution (<2 Å). Comparison of these structures with those of TGFβR1 reveal shared ligand contacts as well as differences in the ATP-binding sites, suggesting strategies for the design of pan and selective TGFβR inhibitors. [ABSTRACT FROM AUTHOR]
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- 2016
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10. Crystal structure of microtubule affinity-regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor.
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Sack, John S., Gao, Mian, Kiefer, Susan E., Myers, Joseph E., Newitt, John A., Wu, Sophie, and Yan, Chunhong
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CRYSTAL structure , *MICROTUBULES , *KINASE inhibitors - Abstract
Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase involved in the phosphorylation of MAP proteins that regulate microtubule dynamics. Abnormal activity of MARK4 has been proposed to contribute to neurofibrillary tangle formation in Alzheimer's disease. The crystal structure of the catalytic and ubiquitin-associated domains of MARK4 with a potent pyrazolopyrimidine inhibitor has been determined to 2.8 Å resolution with an Rwork of 22.8%. The overall structure of MARK4 is similar to those of the other known MARK isoforms. The inhibitor is located in the ATP-binding site, with the pyrazolopyrimidine group interacting with the inter-lobe hinge region while the aminocyclohexane moiety interacts with the catalytic loop and the DFG motif, forcing the activation loop out of the ATP-binding pocket. [ABSTRACT FROM AUTHOR]
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- 2016
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11. Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core.
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Sivaprakasam, Prasanna, Han, Xiaojun, Civiello, Rita L., Jacutin-Porte, Swanee, Kish, Kevin, Pokross, Matt, Lewis, Hal A., Ahmed, Nazia, Szapiel, Nicolas, Newitt, John A., Baldwin, Eric T., Xiao, Hong, Krause, Carol M., Park, Hyunsoo, Nophsker, Michelle, Lippy, Jonathan S., Burton, Catherine R., Langley, David R., Macor, John E., and Dubowchik, Gene M.
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AMINOPYRIDINES , *GLYCOGEN synthase kinase-3 , *PYRIDONE , *BIPOLAR disorder , *TAU proteins , *PHOSPHORYLATION - Abstract
Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer’s disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses. [ABSTRACT FROM AUTHOR]
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- 2015
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12. Discovery of Novel P1 Groupsfor Coagulation FactorVIIa Inhibition Using Fragment-Based Screening.
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Cheney, Daniel L., Bozarth, Jeffrey M., Metzler, William J., Morin, Paul E., Mueller, Luciano, Newitt, John A., Nirschl, Alexandra H., Rendina, Alan R., Tamura, James K., Anzhi Wei, Xiao Wen, Wurtz, Nicholas R., Seiffert, Dietmar A., Wexler, Ruth R., and Priestley, E. Scott
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BLOOD coagulation factor VII , *MOLECULAR docking , *NUCLEAR magnetic resonance , *BIOLOGICAL assay , *HETEROCYCLIC compounds - Abstract
A multidisciplinary,fragment-based screening approach involvingprotein ensemble docking and biochemical and NMR assays is described.This approach led to the discovery of several structurally diverse,neutral surrogates for cationic factor VIIa P1 groups, which are generallyassociated with poor pharmacokinetic (PK) properties. Among the novelfactor VIIa inhibitory fragments identified were aryl halides, lactams,and heterocycles. Crystallographic structures for several bound fragmentswere obtained, leading to the successful design of a potent factorVIIa inhibitor with a neutral lactam P1 and improved permeability. [ABSTRACT FROM AUTHOR]
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- 2015
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13. The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode.
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Wrobleski, Stephen T., Lin, Shuqun, Murali Dhar, T.G., Dyckman, Alaric J., Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Fan, Yi, Doweyko, Arthur M., Tokarski, John S., Kish, Kevin F., Kiefer, Susan E., Sack, John S., Newitt, John A., Witmer, Mark R., McKinnon, Murray, Barrish, Joel C., Dodd, John H., Schieven, Gary L., and Leftheris, Katerina
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KINASE inhibitors , *MITOGEN-activated protein kinases , *X-ray crystallography , *DRUG design , *TARGETED drug delivery - Abstract
Abstract: A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed. [Copyright &y& Elsevier]
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- 2013
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14. Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors
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Dyckman, Alaric J., Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Shen, Ding Ren, McIntyre, Kim W., Gillooly, Kathleen M., Shuster, David J., Doweyko, Arthur M., Sack, John S., Kish, Kevin, Kiefer, Susan E., Newitt, John A., Zhang, Hongjian, Marathe, Punit H., McKinnon, Murray, Barrish, Joel C., Dodd, John H., Schieven, Gary L., and Leftheris, Katerina
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DRUG development , *TRIAZINES , *MITOGEN-activated protein kinases , *KETONES , *DRUG synergism , *CHEMICAL inhibitors , *FUNCTIONAL groups , *INFLAMMATION , *STRUCTURE-activity relationships - Abstract
Abstract: Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation. [Copyright &y& Elsevier]
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- 2011
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15. 5-Amino-pyrazoles as potent and selective p38α inhibitors
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Das, Jagabandhu, Moquin, Robert V., Dyckman, Alaric J., Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Shen, Ding Ren, McIntyre, Kim W., Gillooly, Kathleen, Doweyko, Arthur M., Newitt, John A., Sack, John S., Zhang, Hongjian, Kiefer, Susan E., Kish, Kevin, McKinnon, Murray, Barrish, Joel C., Dodd, John H., Schieven, Gary L., and Leftheris, Katerina
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PYRAZOLES , *STRUCTURE-activity relationships , *SCAFFOLD proteins , *THIAMIN pyrophosphate , *MITOGEN-activated protein kinases , *ENZYME inhibitors - Abstract
Abstract: The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed. [Copyright &y& Elsevier]
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- 2010
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16. Utilization of a nitrogen–sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors
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Lin, Shuqun, Wrobleski, Stephen T., Hynes, John, Pitt, Sidney, Zhang, Rosemary, Fan, Yi, Doweyko, Arthur M., Kish, Kevin F., Sack, John S., Malley, Mary F., Kiefer, Susan E., Newitt, John A., McKinnon, Murray, Trzaskos, James, Barrish, Joel C., Dodd, John H., Schieven, Gary L., and Leftheris, Katerina
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PYRIMIDINES , *MITOGEN-activated protein kinases , *INTERLEUKIN-1 , *TUMOR necrosis factors , *ENZYME inhibitors , *NITROGEN compounds , *SULFUR compounds , *MOLECULE-molecule collisions - Abstract
Abstract: The design, synthesis, and structure–activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen–sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen–sulfur interaction are discussed. [Copyright &y& Elsevier]
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- 2010
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17. Native mass spectrometry and gas-phase fragmentation provide rapid and in-depth topological characterization of a PROTAC ternary complex.
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Song, Jong Hee, Wagner, Nicole D., Yan, Jing, Li, Jing, Huang, Richard Y.-C., Balog, Aaron J., Newitt, John A., Chen, Guodong, and Gross, Michael L.
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MASS spectrometry , *COLLISION induced dissociation , *ELECTRON capture , *ION mobility spectroscopy , *PROTEIN-protein interactions - Abstract
Proteolysis-targeting chimeras (PROTACs) represent a new direction in small-molecule therapeutics whereby a heterobifunctional linker to a protein of interest (POI) induces its ubiquitination-based proteolysis by recruiting an E3 ligase. Here, we show that charge reduction, native mass spectrometry, and gas-phase activation methods combine for an in-depth analysis of a PROTAC-linked ternary complex. Electron capture dissociation (ECD) of the intact POI-PROTAC-VCB complex (a trimeric subunit of an E3 ubiquitin ligase) promotes POI dissociation. Collision-induced dissociation (CID) causes elimination of the nonperipheral PROTAC, producing an intact VCB-POI complex not seen in solution but consistent with PROTAC-induced protein-protein interactions. In addition, we used ion mobility spectrometry (IMS) and collisional activation to identify the source of this unexpected dissociation. Together, the evidence shows that this integrated approach can be used to screen for ternary complex formation and PROTAC-protein contacts and may report on PROTAC-induced protein-protein interactions, a characteristic correlated with PROTAC selectivity and efficacy. • Native MS yields structural analysis of a PROTAC-induced ternary complex • Multiple activation methods probe unique subunit dissociation pathways • Conformational analysis identifies two gas-phase PROTAC complex topologies • Subsequent subunit dissociation interrogates relevant protein-protein interactions Song et al. demonstrate the utility of native mass spectrometry, ion mobility spectrometry, and multiple activation methods to characterize PROTAC-induced complex topologies and conformation-specific protein-protein interactions. [ABSTRACT FROM AUTHOR]
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- 2021
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18. The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)—A potent and efficacious p38α MAP kinase inhibitor
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Hynes, John, Wu, Hong, Pitt, Sidney, Shen, Ding Ren, Zhang, Rosemary, Schieven, Gary L., Gillooly, Kathleen M., Shuster, David J., Taylor, Tracy L., Yang, XiaoXia, McIntyre, Kim W., McKinnon, Murray, Zhang, Hongjian, Marathe, Punit H., Doweyko, Arthur M., Kish, Kevin, Kiefer, Susan E., Sack, John S., Newitt, John A., and Barrish, Joel C.
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INFLAMMATION , *PATHOLOGY , *FOCAL adhesion kinase , *PROTEIN-tyrosine kinases - Abstract
Abstract: A novel structural class of p38α MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38α inhibitor that is orally efficacious in rodent models of acute and chronic inflammation. [Copyright &y& Elsevier]
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- 2008
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19. Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors
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Kim, Kyoung Soon, Lu, Songfeng, Cornelius, Lyndon A., Lombardo, Louis J., Borzilleri, Robert M., Schroeder, Gretchen M., Sheng, Christopher, Rovnyak, George, Crews, Donald, Schmidt, Robert J., Williams, David K., Bhide, Rajeev S., Traeger, Sarah C., McDonnell, Patricia A., Mueller, Luciano, Sheriff, Steven, Newitt, John A., Pudzianowski, Andrew T., Yang, Zheng, and Wild, Robert
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ADENOSINE triphosphatase , *MICROTUBULES , *CELL division , *CELL proliferation - Abstract
Abstract: Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
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20. Inhibitors of human mitotic kinesin Eg5: Characterization of the 4-phenyl-tetrahydroisoquinoline lead series
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Tarby, Christine M., Kaltenbach, Robert F., Huynh, Tram, Pudzianowski, Andrew, Shen, Henry, Ortega-Nanos, Marie, Sheriff, Steven, Newitt, John A., McDonnell, Patricia A., Burford, Neil, Fairchild, Craig R., Vaccaro, Wayne, Chen, Zhong, Borzilleri, Robert M., Naglich, Joseph, Lombardo, Louis J., Gottardis, Marco, Trainor, George L., and Roussell, Deborah L.
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KINESIN , *CHEMICAL inhibitors , *TETRAHYDROISOQUINOLINES , *HETEROCYCLIC compounds - Abstract
Abstract: In a high-throughput screening effort, a series of tetrahydroisoquinolines was identified as modest inhibitors of human Eg5. A medicinal chemistry optimization effort led to the identification of R-4-(3-hydroxyphenyl)-N,N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (32a) as a potent inhibitor of human Eg5 (ATPase IC50 104nM) with good anti-proliferative activity in A2780 cells (IC50 234nM). [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
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