Lorthiois, Edwige, Gerspacher, Marc, Beyer, Kim, Vaupel, Andrea, Leblanc, Catherine, Stringer, Rowan, Weiss, Andreas, Wilcken, Rainer, Guthy, Daniel Alexander, Lingel, Andreas, Bomio-Confaglia, Claudio, Machauer, Rainer, Rigollier, Pascal, Ottl, Johannes, Arz, Dorothee, Bernet, Pascal, Desjonqueres, Gaelle, Dussauge, Solene, Kazic-Legueux, Malika, Lozac'h, Marie-Anne, Mura, Christophe, Sorge, Mickael, Todorov, Milen, Warin, Nicolas, Zink, Florence, Voshol, Johannes, Zecri, Frederic, Sedrani, Richard, Ostermann, Nils and Brachmann, Saskia (2022) JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors. Journal of medicinal chemistry, 65 (24). pp. 16173-16203. ISSN 1520-4804

Abstract

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

Item Type:	Article
Keywords:	Mice Animals Humans Proto-Oncogene Proteins p21(ras) Neoplasms Mutation Drug Design Disease Models, Animal Pyrazoles
Date Deposited:	21 Jan 2023 00:45
Last Modified:	21 Jan 2023 00:45
URI:	https://oak.novartis.com/id/eprint/48106