The protein tyrosine phosphatase SHP2, encoded by the PTPN11 gene, plays a central role in modulating cell survival and growth by transmitting signals from upstream receptor tyrosine kinases, or RTKs, to RAS. As a key signaling node within the RAS pathway, SHP2 acts as an important regulator of growth signals within normal cells and, in certain circumstances, cancer cells. Here we describe identification of RMC-4550, a potent, selective and orally bioavailable SHP2 inhibitor, a high quality tool compound suitable to study the role of SHP2 in tumor biology, both in vitro and in vivo. Continuous SAR studies on RMC-4550 and other series enabled the discovery of our Clinical Candidate, RMC-4630 that has desirable drug-like properties for clinical development. Consistent with preclinical observations, initial data from a phase 1 trial of RMC-4630 showed well behaved pharmacokinetic and tolerability profiles, and anti-tumor activity in tumors harboring diverse mutations in the RAS pathway including KRASG12C, KRASG12D, NF1LOF, and BRAF Class 3. Clinical evaluation of the investigational agent RMC-4630 as a both a single agent and in combination with companion inhibitors is ongoing, with additional combination studies planned.

Discovery and development of allosteric inhibitors of SHP2.

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.