Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRAS(G12C)

Covalent inhibitors of KRAS(G12C) have shown antitumor activity against advanced/metastatic KRAS(G12C)-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRAS(G12C) that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRAS(G12C)-driven cellular signaling and demonstrates selective antiproliferative activity in KRAS(G12C)-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRAS(G12C)-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRAS(G12C)-mutated tumors. SIGNIFICANCE: JDQ443 is a structurally novel covalent KRAS(G12C) inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRAS(G12C)-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. See related video: https://vimeo.com/720726054 This article is highlighted in the In This Issue feature, p. 1397