RMC-4630 — Investigational Agent
SHP2 Inhibitor · Phase 1/2 · Revolution Medicines
Mechanism of Action
Allosteric, selective inhibitor of SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase 2; encoded by PTPN11). SHP2 is a non-receptor protein tyrosine phosphatase that acts as a positive regulator of RAS/MAPK signaling, functioning downstream of multiple receptor tyrosine kinases (EGFR, MET, FGFR, HER2) and upstream of RAS. SHP2 is required for SOS1-mediated RAS nucleotide exchange (GTP loading) in response to growth factor stimulation. By binding the "tunnel" between the N-SH2 and PTP domains in an auto-inhibited conformation and preventing its activation, RMC-4630 blocks the…
Investigational Indications
- KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) — in combination with MRTX1133 (KRAS G12D inhibitor)
- KRAS-mutant NSCLC — combination strategies with KRAS G12C inhibitors
- RAS/MAPK pathway-driven solid tumors with RTK-mediated feedback as a resistance mechanism
- Neurofibromatosis type 1 (NF1)-mutant tumors (NF1 loss activates RAS; SHP2 inhibition may suppress downstream signaling)