posted on 2023-09-29, 20:07authored byAlexander M. Taylor, Bret R. Williams, Fabrizio Giordanetto, Elizabeth H. Kelley, André Lescarbeau, Kelley Shortsleeves, Yong Tang, W. Patrick Walters, Alfonso Arrazate, Christine Bowman, Erin Brophy, Emily W. Chan, Gauri Deshmukh, Jack B. Greisman, Thomas L. Hunsaker, D. Randal Kipp, Pablo Saenz Lopez-Larrocha, Danilo Maddalo, Iain J. Martin, Paul Maragakis, Mark Merchant, Mark Murcko, Hunter Nisonoff, Vi Nguyen, Vy Nguyen, Olivia Orozco, Christopher Owen, Levi Pierce, Molly Schmidt, David E. Shaw, Sherri Smith, Eric Therrien, John C. Tran, Jim Watters, Nigel J. Waters, Jeremy Wilbur, Lindsay Willmore
Protein
tyrosine phosphatase SHP2 mediates RAS-driven
MAPK signaling
and has emerged in recent years as a target of interest in oncology,
both for treating with a single agent and in combination with a KRAS
inhibitor. We were drawn to the pharmacological potential of SHP2
inhibition, especially following the initial observation that drug-like
compounds could bind an allosteric site and enforce a closed, inactive
state of the enzyme. Here, we describe the identification and characterization
of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently
in clinical trials in combination with KRAS G12C inhibitor divarasib
(GDC-6036) for the treatment of solid tumors driven by a KRAS G12C
mutation.