An Expert Report on WDB-178: A Preclinical Investigational Agent Targeting KRAS G12C

1. Executive Summary

WDB-178 is an investigational therapeutic agent in the preclinical phase of development, originated by Revolution Medicines, Inc..[1] It is classified as a non-degrading molecular glue and is designed to target the oncogenic KRAS G12C protein, a well-validated driver in various human cancers. The mechanism of action of WDB-178 is understood to be as a KRAS G12C inhibitor, operating through Revolution Medicines' proprietary tri-complex inhibitor platform.[2] This platform distinctively targets the active, GTP-bound conformation of RAS proteins, commonly referred to as RAS(ON). The therapeutic strategy involves inducing the formation of a ternary complex comprising WDB-178, an intracellular chaperone protein (such as cyclophilin A), and the RAS(ON) target protein. This tri-complex formation is intended to sterically hinder the interaction of KRAS G12C(ON) with its downstream effector proteins, thereby abrogating oncogenic signaling pathways.[4]