Michael P. Dwyer
Merck & Co.
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Featured researches published by Michael P. Dwyer.
Molecular Cancer Therapeutics | 2010
David Parry; Timothy J. Guzi; Frances Shanahan; Nicole Davis; Deepa Prabhavalkar; Derek Wiswell; Wolfgang Seghezzi; Kamil Paruch; Michael P. Dwyer; Ronald J. Doll; Amin A. Nomeir; William T. Windsor; Thierry O. Fischmann; Yaolin Wang; Martin Oft; Taiying Chen; Paul Kirschmeier; Emma Lees
Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC50 values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. Mol Cancer Ther; 9(8); 2344–53. ©2010 AACR.
Molecular Cancer Therapeutics | 2011
Timothy J. Guzi; Kamil Paruch; Michael P. Dwyer; Marc Labroli; Frances Shanahan; Nicole Davis; Lorena Taricani; Derek Wiswell; Wolfgang Seghezzi; Ervin Penaflor; Bhagyashree Bhagwat; Wei Wang; Danling Gu; Yunsheng Hsieh; Suining Lee; Ming Liu; David Parry
Checkpoint kinase 1 (CHK1) is an essential serine/threonine kinase that responds to DNA damage and stalled DNA replication. CHK1 is essential for maintenance of replication fork viability during exposure to DNA antimetabolites. In human tumor cell lines, ablation of CHK1 function during antimetabolite exposure led to accumulation of double-strand DNA breaks and cell death. Here, we extend these observations and confirm ablation of CHK2 does not contribute to these phenotypes and may diminish them. Furthermore, concomitant suppression of cyclin-dependent kinase (CDK) activity is sufficient to completely antagonize the desired CHK1 ablation phenotypes. These mechanism-based observations prompted the development of a high-content, cell-based screen for γ-H2AX induction, a surrogate marker for double-strand DNA breaks. This mechanism-based functional approach was used to optimize small molecule inhibitors of CHK1. Specifically, the assay was used to mechanistically define the optimal in-cell profile with compounds exhibiting varying degrees of CHK1, CHK2, and CDK selectivity. Using this approach, SCH 900776 was identified as a highly potent and functionally optimal CHK1 inhibitor with minimal intrinsic antagonistic properties. SCH 900776 exposure phenocopies short interfering RNA-mediated CHK1 ablation and interacts synergistically with DNA antimetabolite agents in vitro and in vivo to selectively induce dsDNA breaks and cell death in tumor cell backgrounds. Mol Cancer Ther; 10(4); 591–602. ©2011 AACR.
Journal of Pharmacology and Experimental Therapeutics | 2007
Waldemar Gonsiorek; Xuedong Fan; David Hesk; James Fossetta; Hongchen Qiu; James Jakway; M. Motasim Billah; Michael P. Dwyer; Jianhua Chao; Gregory Deno; Art Taveras; Daniel Lundell; R. William Hipkin
In neutrophils, growth-related protein-α (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27–36, 2001; Biochemistry 42:2874–2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the pharmacology of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Sch527123), a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [3H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (Kd = 3.9 ± 0.3 nM), the compound is CXCR2-selective (Kd = 0.049 ± 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.
ACS Medicinal Chemistry Letters | 2010
Kamil Paruch; Michael P. Dwyer; Carmen Alvarez; Courtney Brown; Tin-Yau Chan; Ronald J. Doll; Kerry Keertikar; Chad E. Knutson; Brian Mckittrick; Jocelyn Rivera; Randall R. Rossman; Greg Tucker; Thierry O. Fischmann; Alan Hruza; Vincent Madison; Amin A. Nomeir; Yaolin Wang; Paul Kirschmeier; Emma Lees; David Parry; Nicole Sgambellone; Wolfgang Seghezzi; Lesley Schultz; Frances Shanahan; Derek Wiswell; Xiaoying Xu; Quiao Zhou; Ray Anthony James; Vidyadhar M. Paradkar; Haengsoon Park
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
Bioorganic & Medicinal Chemistry Letters | 2011
Michael P. Dwyer; Kamil Paruch; Marc Labroli; Carmen Alvarez; Kerry Keertikar; Cory Poker; Randall R. Rossman; Thierry O. Fischmann; Jose S. Duca; Vincent Madison; David Parry; Nicole Davis; Wolfgang Seghezzi; Derek Wiswell; Timothy J. Guzi
Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.
Bioorganic & Medicinal Chemistry Letters | 2008
Younong Yu; Michael P. Dwyer; Jianping Chao; Cynthia J. Aki; Jianhua Chao; Biju Purakkattle; Diane Rindgen; Richard W. Bond; Rosemary Mayer-Ezel; James Jakway; Hongchen Qiu; R. William Hipkin; James Fossetta; Waldemar Gonsiorek; Hong Bian; Xuedong Fan; Carol Terminelli; Jay S. Fine; Daniel Lundell; J. Robert Merritt; Zhenmin He; Gaifa Lai; Minglang Wu; Arthur G. Taveras
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.
Bioorganic & Medicinal Chemistry Letters | 2016
Anilkumar G. Nair; Qingbei Zeng; Oleg Selyutin; Stuart B. Rosenblum; Yueheng Jiang; De-Yi Yang; Kerry Keertikar; Guowei Zhou; Michael P. Dwyer; Seong Heon Kim; Bandarpalle B. Shankar; Wensheng Yu; Ling Tong; Lei Chen; Robert Mazzola; John P. Caldwell; Haiqun Tang; Melissa L. Allard; Ronald N. Buckle; Polivina Jolicia F Gauuan; Christian L. Holst; Gregory Scott Martin; Kannan P. Naicker; Samuel Vellekoop; Sony Agrawal; Rong Liu; Rong Kong; Paul Ingravallo; Ellen Xia; Ying Zhai
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
Bioorganic & Medicinal Chemistry Letters | 2009
Purakkattle J. Biju; Arthur G. Taveras; Michael P. Dwyer; Younong Yu; Jianhua Chao; R. William Hipkin; Xuedong Fan; Diane Rindgen; Jay S. Fine; Daniel Lundell
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various fluoroalkyl groups as alpha side chain were prepared and found to show significant improvements in the binding affinities towards both CXCR2 and CXCR1 receptors.
Bioorganic & Medicinal Chemistry Letters | 2009
Cynthia J. Aki; Jianping Chao; Johan A. Ferreira; Michael P. Dwyer; Younong Yu; Jianhua Chao; Robert J. Merritt; Gaifa Lai; Minglang Wu; R. William Hipkin; Xuedong Fan; Waldemar Gonsiorek; James Fosseta; Diane Rindgen; Jay S. Fine; Daniel Lundell; Arthur G. Taveras; Purakkattle J. Biju
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various amide modifications and substitution on the left side phenyl ring were prepared and found to show significant inhibitory activities towards both CXCR2 and CXCR1 receptors.
Bioorganic & Medicinal Chemistry Letters | 2016
Wensheng Yu; Craig A. Coburn; Anilkumar G. Nair; Michael Wong; Stuart B. Rosenblum; Guowei Zhou; Michael P. Dwyer; Ling Tong; Bin Hu; Bin Zhong; Jinglai Hao; Tao Ji; Shuai Zan; Seong Heon Kim; Qingbei Zeng; Oleg Selyutin; Lei Chen; Frédéric Massé; Sony Agrawal; Rong Liu; Ellen Xia; Ying Zhai; Stephanie Curry; Patricia McMonagle; Paul Ingravallo; Ernest Asante-Appiah; Mingxiang Lin; Joseph A. Kozlowski
Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45-47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.