Chemical Consultants Network ZOOM MEETING

STEREOCHEMICAL DISCRIMINATION OF A COVALENT, IRREVERSIBLE WERNER HELICASE INHIBITOR SERIES

Dennis Murphy PhD, Principal Investigator at GSK

DATE & TIME: May 14, 2025 6:30 PM

Abstract: The presentation will cover a drug discovery project, illustrating the utility of in-depth analysis of the structure and corresponding behavior of molecules that are early in the optimization phase. The Werner helicase is a synthetic lethality target for MicroSatellite Instability-High/Mis-Match Repair Deficient (MSI-H/dMMR) cancers, identified through genome-wide screening of genetic dependencies and CRISPR rescue. Its primary function is resolving a wide variety of DNA lesions. In-house screening identified three covalent inhibitors that alkylated cysteine-727. One compound containing a tricyclic core was optimized with a cyclic vinylsulfone warhead, yielding four compounds differing only in the configuration of the two stereogenic centers. Kinetic results were fit to a two-step, irreversible inhibition model. The bimolecular inactivation rate showed a nearly 500-fold potency range for the four compounds. The x-ray structure of the most potent analog was solved and showed a binding pocket for the tricycle and a covalent bond between cys-727 and the warhead. Modeling of the three weaker stereoisomers showed that a hydrogen bond with a nearby arginine and the proximity of the electronegative sulfone likely contributed to the variation in potency. While there were significant differences in the absolute binding and inactivation rates of the four analogs against the apo-enzyme versus the actively unwinding helicase, the rank order of the compounds remained the same 

Biography: Dennis Murphy is currently a Principal Investigator at GSK in Discovery Biology. His work is focused on early drug discovery, primarily against enzyme targets. He utilizes enzymology and biophysics to dissect the mechanism of inhibition for lead-optimization. Dennis’s undergraduate degree is from Bucknell University with a double major in Biology and Chemistry. He earned his Ph.D. in organic chemistry at the University of Wisconsin and was a post-doctoral fellow at Penn State University. He has spent the majority of his career in pharmaceutical research, but also worked in biocatalysis and enzyme evolution, bioinformatics, nanomaterials, and adjunct teaching, all in the Philadelphia area.

Reservation: Use the register button to register for this meeting. The Zoom link will arrive via email

Location:  Online via Zoom! (registration required)