Steven S. Carroll
Merck & Co.
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Featured researches published by Steven S. Carroll.
Antimicrobial Agents and Chemotherapy | 2012
Vincenzo Summa; Steven W. Ludmerer; John A. McCauley; Christine Fandozzi; Christine Burlein; Giuliano Claudio; Paul J. Coleman; Jillian DiMuzio; Marco Ferrara; Marcello Di Filippo; Adam T. Gates; Donald J. Graham; Steven Harper; Daria J. Hazuda; Carolyn McHale; Edith Monteagudo; Vincenzo Pucci; Michael Rowley; Michael T. Rudd; Aileen Soriano; Mark W. Stahlhut; Joseph P. Vacca; David B. Olsen; Nigel Liverton; Steven S. Carroll
ABSTRACT HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.
Proceedings of the National Academy of Sciences of the United States of America | 2017
Hua-Poo Su; Keith Rickert; Christine Burlein; Kartik Narayan; Marina Bukhtiyarova; Danielle M. Hurzy; Craig A. Stump; Xu-Fang Zhang; John Reid; Alicja Krasowska-Zoladek; Srivanya Tummala; Jennifer M. Shipman; Maria Kornienko; Peter Lemaire; Daniel Krosky; Amanda Heller; Abdelghani Abe Achab; Chad Chamberlin; Peter Saradjian; Berengere Sauvagnat; Xianshu Yang; Michael Ziebell; Elliott Nickbarg; John M. Sanders; Mark T. Bilodeau; Steven S. Carroll; Kevin J. Lumb; Stephen M. Soisson; Darrell A. Henze; Andrew John Cooke
Significance Signal transduction through Tropomyosin-related kinase A (TrkA), a receptor tyrosine kinase, is a target for inhibition of chronic pain and could lead to a new class of drugs against pain. Selectivity against kinases can be difficult to achieve, especially against members of the same kinase family. Structures of the compounds bound to TrkA show a binding site comprised of the kinase, which is conserved among the Trk family, and the juxtamembrane (JM), which is not well conserved. Depending on their chemical substructure, the region of the juxtamembrane that interacts with the compounds can be different, leading to differences in specificity. This study emphasizes the importance of including residues beyond the catalytic domain for small-molecule screening, importance of screening by affinity, and structural characterization to understand binding interactions. Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of—but adjacent to—the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.
Archive | 2002
Balkrishen Bhat; Neelima Bhat; Anne B. Eldrup; Thazha P. Prakash; Marija Prhavc; Quanlai Song; Phillip Dan Cook; Steven S. Carroll; Malcolm Maccoss; David B. Olsen
Archive | 2002
Balkrishen Bhat; Neelima Bhat; Anne B. Eldrup; Thazha P. Prakash; Marija Prhavc; Quanlai Song; Phillip Dan Carlsbad Cook; Steven S. Carroll; Malcolm Maccoss; David B. Olsen
Journal of Medicinal Chemistry | 2003
James C. Barrow; Philippe G. Nantermet; Shaun R. Stauffer; Phung L. Ngo; Melissa A. Steinbeiser; Shi-shan Mao; Steven S. Carroll; Carolyn Bailey; Dennis Colussi; Michelle Bosserman; Christine Burlein; Jacquelynn J. Cook; Gary R. Sitko; Philip R. Tiller; Cynthia Miller-Stein; Mark Rose; Daniel R. McMasters; Joseph P. Vacca; Harold G. Selnick
Archive | 2004
David B. Olsen; Joanne E. Tomassini; Shi-shan Mao; Steven S. Carroll
Angewandte Chemie | 2008
John A. Mccauley; Michael T. Rudd; Kevin T. Nguyen; Charles J. McIntyre; Joseph J. Romano; Kimberly J. Bush; Sandor L. Varga; Charles Ross; Steven S. Carroll; Jillian DiMuzio; Mark W. Stahlhut; David B. Olsen; Terry A. Lyle; Joseph P. Vacca; Nigel J. Liverton
Analytical Biochemistry | 2001
Wei Zheng; Steven S. Carroll; James Inglese; Robert Graves; Leighton Howells; Berta Strulovici
Archive | 2006
Steven S. Carroll; David B. Olsen
Archive | 2012
Steven S. Carroll; John A. McCauley; David B. Olsen; Vincenzo Summa; Michael Rowley; Mark W. Stahlhut; Daria J. Hazuda