Cancer Discov candisc.0158.2022.
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRAS 46 G12C-mutated cancers, though resistance emerges and additional strategies are needed to improve 47 outcomes. JDQ443 is a structurally unique, covalent inhibitor of GDP-bound KRASG12C that forms 48 novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular 49 signaling and demonstrates selective antiproliferative activity in KRAS G12C-mutated cell lines, 50 including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven 51 antitumor efficacy in KRAS G12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor 52 xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with SHP2, 53 MEK or CDK4/6 inhibitors. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is 54 maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. 55 JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both 56 strategies showing antitumor activity in patients with KRAS G12C-mutated tumors.