Project Summary:
PI - D Perlin, Rutgers University
Project title – Center to develop therapeutic countermeasures to high-threat bacetrial agents
Cubist summary - There is an unmet medical need for new therapies against serious G+ and G- infections utilizing a novel mechanism of action because of increasing resistance development to the current marketed antibiotics. Bacetrial DNA gyrase (GyrA/GyrB subunits) and topoisomerase IV (ParC/ParE subunits) are involved in supercoiling and relaxing DNA. These are well established antibacetrial targets with marketed drugs such as the fluoroquinolones (FQ) that target the DNA binding site and the natural product novobiocin that inhibits the ATPase activity of GyrB/ParE subunits. Targeting gyrase in different ways, like using alternative chemical matter at the DNA or ATP binding site, could result in a new antibiotic with activity against resistant strains. GyrB/ParE inhibitors include natural products and fully synthetic compounds developed by structure-based drug design (SBDD). Through the acquisition of Trius Therapeutics, Cubist has access to a novel series of dual GyrB/ParE enzyme inhibitors 1. These molecules are the result of an intensive and iterative SBDD program utilizing crystal structures of GyrB from E. faecalis to maximize binding interactions in the ATP binding site. These compounds have been shown to be very potent (down to ng/ml MIC in some species) across a variety of commercially relevant and biodefense pathogens with demonstrated efficacy in several animal models of infection. These agents uniformly demonstrate exquisite G+ activity. Many agents displaying a basic amine at R2 have unprecedented broad spectrum G+ and G- activity, including Pa. The tricyclic structure-activity relationship data was mined to identify the more promising molecules for resynthesis and further in vitro and in vivo profiling including: MICs, hERG, selectivity, PK, MTD, RI and efficacy in appropriate animal model(s). These data, in combination with other studies at Cubist, will help define a therapeutic index for selected molecules and serve to support one or more target product profiles.
Biography:
Dr. David S. Perlin, PhD is Executive Director of the Rutgers/New Jersey Medical School’s Public Health Research Institute (PHRI), a 72 year old specialized center for global infectious diseases research. He is also Director of the Rutgers Regional Biocontainment Laboratory, one of thirteen NIH-designated national centers, and a Professor of Microbiology and Molecular Genetics. Dr. Perlin helped establish PHRI as a leading tuberculosis and opportunistic infections research organization. His primary expertise is in fungal infections, mechanisms of antifungal drug resistance, and rapid diagnosis of opportunistic drug resistant bacterial and fungal pathogens in high-risk patients. He has published more than 175 papers and book chapters and has co-authored two books. His laboratory is supported by grants from the NIH, pharma and biotech sectors. He is on the editorial board of several scientific journals and serves on the Board of Directors of the Aaron Diamond AIDS Research Center, and Scientific/Medical Advisory Boards for the CLSI, pharma and biotech companies, and PinnacleCare. He is also a member of the New York City Department of Health and Mental Hygiene Advisory Panel on Bioterrorism and Emerging Infections, the Executive Committee of the Northeast Biodefense Center, and Steering Committee for Microbiology, Immunology & Infectious Diseases of the New York Academy of Sciences.
Dr. Perlin earned an AB degree from Brandeis University in 1976 and a Ph.D. from Cornell University in 1980. He pursued postdoctoral studies at the Yale University School of Medicine and the University of Rochester School of Medicine and Dentistry. Dr. Perlin joined PHRI in 1985; he was named Scientific Director in 1992, President in 2005, and Director of the new PHRI Center in 2006. He was appointed Professor of Microbiology and Molecular Genetics in 2003 and Executive Director of PHRI and the Rutgers Regional Biocontainment Laboratory in 2010. Dr. Perlin was named a Fellow of the New York Academy of Sciences in 2005, and a Visiting Professor at the University of Manchester, UK in 2009.
Contact info:
David Perlin PhD
Executive Director and Professor
Public Health Research Institute Center
New Jersey Medical School - Rutgers, The State University of New Jersey
225 Warren Street
Newark, New Jersey 07103
Phone: (973) 854-3200
Fax: 973-854-3201
e-mail: perlinds@njms.rutgers.edu
Biography:
Roland E. Dolle, Ph.D., is Sr. Director of medicinal chemistry at Cubist Pharmaceuticals since 2011 and is responsible for co-leading the department within Cubist Research and Development. Dr. Dolle is an experienced medicinal chemist and scientific leader with a strong record of success in drug design, team leadership, candidate selection, preclinical development and registration. Current research interests include the discovery of antibiotics and pain therapeutics for acute care. Prior to joining Cubist, Dr. Dolle held leadership positions at Adolor Corporation (2000-2010), Pharmacopeia, Inc. (1994-2000), Sterling Winthrop (1990-1994) and GlaxoSmithKline (1985-1990). Dr. Dolle received his Ph.D. in organic chemistry at the University of Pennsylvania. Dr. Dolle has advanced 17 drug candidates into preclinical/clinical development; author of 245 abstracts/publications, and inventor on 70 issued US patents.
Contact info:
Ron Dolle, PhD
e-mail: roland.e.dolle@gmail.com
https://www.linkedin.com/in/rolanddolle
