ArticleCancer discovery2022
Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 132 citations in OpenAlex.
- Review
- Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants.Nature chemical biology · 2026Article
- Development of a PK/PD-Efficacy Modeling Framework for Covalent Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model.Nature communications · 2026Article
- RAS Inhibitors: Changing the Paradigm from the Undruggable.Pharmaceutics · 2026Review
- Study of the blood-brain barrier-penetrating KRAS G12C inhibitor JMKX1899 in KRAS G12C-mutated NSCLC with brain metastases.Journal of the National Cancer Center · 2026Article
- Systematic and precise interventions for KRAS-mutant cancers.Experimental hematology & oncology · 2026Review
- Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C.Journal of medicinal chemistry · 2026Article
- The GENEVA platform models tumor mosaicism to reveal variations of responses to KRAS inhibitors and identify improved drug combinations.Nature cancer · 2026Article
- Harnessing PDX and PDX 2.0: the next-generation paradigm for precision oncology and translational breakthroughs.Molecular cancer · 2026Review
- Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C.Nature communications · 2026Article
- USP10-mediated deubiquitination and activation ofActa pharmaceutica Sinica. B · 2026Article
- Unravelling Resistance: Integrating Metabolism, Epigenetics, Immunology, and Proteostasis in Strategies against Kirsten Rat Sarcoma Viral Oncogene Homolog-mutant Colorectal Cancer.International journal of biological sciences · 2026Review
- Identification and characterization of binders to a cryptic and functional pocket in KRAS.Nature communications · 2025Article
- Advances in Targeted Therapy for Non-Small-Cell Lung Cancer: Current Progress and Future Directions.International journal of molecular sciences · 2025Review
- Single-cell multi-omics in biliary tract cancers: decoding heterogeneity, microenvironment, and treatment strategies.Molecular biomedicine · 2025Review
- EGFR blockade confers sensitivity to pan-RAS inhibitors in KRAS-mutated cancers.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Novel paradigms in KRAS targeting: Unveiling strategies to combat drug resistance.Chinese medical journal · 2025Review
- Deciphering the differential impact of CDK4 mutations on abemaciclib binding in oral squamous cell carcinoma: a precision medicine approach.Irish journal of medical science · 2025Article
- Binding modes of the KRAS(G12C) inhibitors GDC-6036 and LY3537982 revealed by all atom molecular dynamics simulations.Scientific reports · 2025Article
17 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
39 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-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 KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-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 KRASG12C-mutated tumors. SIGNIFICANCE: JDQ443 is a structurally novel covalent KRASG12C 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 KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.