Dual Plasmepsin IX/X Inhibitors: An Antimalarial Drug Discovery Collaboration

Vials in chemistry lab

Department of Chemistry and Chemical Biology

Location: Peirce 116

Speaker: John A. McCauley, Ph.D., Senior Director, Medicinal Chemistry, Merck, West Point, PA

Abstract

Drug resistance to first-line antimalarials is increasing, resulting in a critical need for the discovery of new malaria treatments with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Welcome Trust, a phenotypic screen of Merck’s aspartyl protease inhibitor library identified a series of inhibitors of a new target, plasmepsin X (PMX). Early exploration of this series, aided by use of a PMX homology model, resulted in the discovery of leads that also inhibit plasmepsin IX (PMIX), another essential aspartic protease. Further potency and PK profile optimization yielded WM-382, a potent dual PMIX/X inhibitor with robust in vivo efficacy at multiple stages of the malaria parasite lifecycle and with an excellent resistance profile.

Biography

John McCauley

Over the past 25 years, John and his group have been involved in the design and synthesis of fifteen compounds entering clinical development, including the combination therapy for the treatment of hepatitis C virus infection, ZEPATIER (elbasvir/grazoprevir), and HCV NS3/4a protease inhibitor VANIHEP (vaniprevir). He currently leads Neglected Tropical Disease Chemistry at Merck. John was awarded the Gordon E. Moore Medal from the Society of Chemical Industry in 2015 and was recognized with an American Chemical Society Heroes of Chemistry Award in 2017 as part of the ZEPATIER team. John graduated from Swarthmore College in 1991, received a Ph.D. in organic chemistry from the University of Pennsylvania, and was an NIH postdoctoral fellow at Harvard University.