2. Academic Validation
  3. JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors

JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors

  • J Med Chem. 2022 Dec 22;65(24):16173-16203. doi: 10.1021/acs.jmedchem.2c01438.
Edwige Lorthiois 1,  Marc Gerspacher 1,  Kim S Beyer 1,  Andrea Vaupel 1,  Catherine Leblanc 1,  Rowan Stringer 1,  Andreas Weiss 1,  Rainer Wilcken 1,  Daniel A Guthy 1,  Andreas Lingel 1,  Claudio Bomio-Confaglia 1,  Rainer Machauer 1,  Pascal Rigollier 1,  Johannes Ottl 1,  Dorothee Arz 1,  Pascal Bernet 2,  Gaëlle Desjonqueres 1,  Solene Dussauge 1,  Malika Kazic-Legueux 1,  Marie-Anne Lozac'h 1,  Christophe Mura 1,  Mickaël Sorge 1,  Milen Todorov 1,  Nicolas Warin 1,  Florence Zink 1,  Hans Voshol 1,  Frederic J Zecri 3,  Richard C Sedrani 1,  Nils Ostermann 1,  Saskia M Brachmann 1,  Simona Cotesta 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, BaselCH-4056, Switzerland.
  • 2 Novartis Pharma AG, BaselCH-4056, Switzerland.
  • 3 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts02139, United States.
PMID: 36399068 DOI: 10.1021/acs.jmedchem.2c01438
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).

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