Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors

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.