JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS G12C for the Treatment of Solid Tumors
Abstract
Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRAS G12C 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 KRAS G12C 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 KRAS G12C 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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JDQ-443 is a selective covalent inhibitor of KRASG12C developed by Novartis.
“JDQ-443 (7), a selective covalent inhibitor of KRASG12C developed by Novartis, was officially registered for clinical trials in January 2021.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [72]
JDQ-443 covalently binds to the "Switch II pocket" of KRASG12C and irreversibly locks it into an inactive GDP binding state.
“In order to overcome the resistance of other KRASG12C inhibitors, JDQ-443 covalently binds to the “Switch II pocket” of KRASG12C and irreversibly locks it into an inactive GDP binding state.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [72]
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References 36 · Cited by 110
- Authors
- Lorthiois, E., Gerspacher, M., Beyer, K. S., Vaupel, A., Leblanc, C., Stringer, R., Weiss, A., Wilcken, R., Guthy, D. A., Lingel, A., Bomio-Confaglia, C., Machauer, R., Rigollier, P., Ottl, J., Arz, D., Bernet, P., Desjonqueres, G., Dussauge, S., Kazic-Legueux, M., Lozac’h, M.-A., Mura, C., Sorge, M., Todorov, M., Warin, N., Zink, F., Voshol, H., Zecri, F. J., Sedrani, R. C., Ostermann, N., Brachmann, S. M., & Cotesta, S.
- Affiliations
- Novartis (Switzerland) (CH)
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts02139, United States
- Corresponding author
- Cotesta, Simona
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-11-18
- Volume
- 65
- Issue
- 24
- Pages
- 16173-16203
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W4309368997
- Cited by
- 110
- References
- 36
- Citations by year
- 2026: 27 · 2025: 23 · 2024: 29 · 2023: 31
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis Pharmaceuticals Corporation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, covalent inhibitors, pyrazole derivatives, atropisomers, tumor resistance, structure-based drug design, anticancer activity, solid tumors, pharmacokinetics/pharmacodynamics
- MeSH terms
- Animals, Disease Models, Animal, Humans, Mutation, Neoplasms, Pyrazoles, Drug Design, Proto-Oncogene Proteins p21(ras), Mice
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