Weiss, Andreas, Lorthiois, Edwige, Barys, Louise, Beyer, Kim, Bomio-Confaglia, Claudio, Burks, Heather, Chen, Xueying, Cui, Xiaoming, de Kanter, Ruben, Dharmarajan, Lekshmi, Fedele, Carmine, Gerspacher, Marc, Guthy, Daniel Alexander, Head, Victoria, Jaeger, Ashley, Jimenez Nunez, Eloisa, Kearns, Jeff, Leblanc, Catherine, Maira, Michel, Murphy, Jason, Oakman, Helen, Ostermann, Nils, Ottl, Johannes, Rigollier, Pascal, Roman, Danielle, Schnell, Christian, Sedrani, Richard, Shimizu, Toshio, Stringer, Rowan, Vaupel, Andrea, Voshol, Johannes, Wessels, Peter, Widmer, Toni, Wilcken, Rainer, Xu, Kun, Zecri, Frederic, Farago, Anna, Cotesta, Simona and Brachmann, Saskia (2022) Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, highly potent, selective covalent oral inhibitor of KRASG12C. Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, highly potent, selective covalent oral inhibitor of KRASG12C.

Abstract

Covalent inhibitors of KRASG12C 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 KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-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 SHP2, MEK or CDK4/6 inhibitors. 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.

Item Type:	Article
Keywords:	JDQ443, NVP-JDQ443, TNO155, NVP-TNO155, RAS, KRAS, KRASG12C
Date Deposited:	13 Sep 2022 00:46
Last Modified:	13 Sep 2022 00:46
URI:	https://oak.novartis.com/id/eprint/46756