1. KRAS inhibitors: going noncovalent
- Author
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Matthias Drosten, Mariano Barbacid, European Research Council, Fundación CRIS contra el Cáncer, Centro de Investigación Biomédica en Red Cáncer (España), and AXA Research Fund
- Subjects
Cancer Research ,General Medicine ,Colorectal cancer ,Piperazines ,Pancreatic ductal adenocarcinoma ,Proto-Oncogene Proteins p21(ras) ,Oncology ,Mutation ,Genetics ,Molecular Medicine ,Humans ,Combination therapies ,KRASG12D ,Noncovalent binding ,Colorectal Neoplasms - Abstract
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 KRASG12C inhibitor adagrasib, Hallin et al. have now, through multiple rounds of structure-based drug design, identified and validated a potent, selective, and noncovalent KRASG12D inhibitor, MRTX1133. This study demonstrated that MRTX1133 inhibited both the inactive and active state of KRASG12D 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., This work was supported by grants from the European Research Council (ERC-2015-AdG/695566, THERACAN), the CRIS Cancer Foundation and the CIBERONC to M.B. M.B. is a recipient of an Endowed Chair from the AXA Research Fund.
- Published
- 2022