KRAS inhibitors: going noncovalent
Open accessAbstract
KRASG12D is the most frequent KRAS mutation in human cancer with particularly high frequencies in pancreatic and colorectal cancer. Informed by the structure of the KRAS G12C inhibitor adagrasib, Hallin et al. have now, through multiple rounds of structure‐based drug design, identified and validated a potent, selective, and noncovalent KRAS G12D inhibitor, MRTX1133. This study demonstrated that MRTX1133 inhibited both the inactive and active state of KRAS G12D and showed potent antitumor activity in several preclinical models of pancreatic and colorectal cancer, especially when combined with cetuximab, a monoclonal antibody against the EGFR, or BYL‐719, a potent PI3Kα inhibitor.
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MRTX-1133 inhibited KRAS-dependent signaling and promoted tumor regression in xenograft models.
“Besides, MRTX-1133 inhibited KRAS-dependent signaling and promoted tumor regression in xenograft models.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [257]
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Cites
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
- Authors
- Drosten, M., & Barbacid, M.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Drosten, Matthias
- Barbacid, Mariano
- Venue
- Molecular Oncology
- Publisher
- Wiley
- Published
- 2022-11-27
- Volume
- 16
- Issue
- 22
- Pages
- 3911-3915
- ISSN
- 1574-7891 (ISSN-L)
- 1878-0261
- PMC
- PMC9718111
- OpenAlex
- W4309165999
- Cited by
- 13
- References
- 15
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 3
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- AXA Research Fund
- CRIS Cancer Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- KRAS G12D, MRTX1133, adagrasib, structure-based drug design, pancreatic cancer, colorectal cancer, cetuximab, EGFR, PI3Kα inhibitor, combination therapy, KRAS mutation
- MeSH terms
- Acetonitriles, Humans, Mutation, Piperazines, Pyrimidines, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras)
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