TY - JOUR
T1 - Glimmers of hope for targeting oncogenic KRAS-G12D
AU - Tang, Daolin
AU - Kang, Rui
N1 - Funding Information:
Research by D.T. and R.K. was supported by grants from the National Institutes of Health (R01CA160417, R01CA229275, and R01CA211070).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/3
Y1 - 2023/3
N2 - KRAS mutations are one of the most common genetic abnormalities in cancer, especially lung, colon, and pancreatic cancers. Strategies targeting the oncogenic KRAS pathway include direct and indirect approaches. KRAS-G12C inhibitors developed based on binding to the switch II pocket structure of KRAS mutant protein represent a breakthrough in the development of targeted therapeutic strategies against oncogenic proteins previously considered undruggable. The covalent KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are used to treat patients with KRAS-G12C-mutated non-small cell lung cancer. Emerging research shows that other host point mutations in KRAS can also be directly targeted by small-molecule compounds. Recently, through extensive structure-based drug design from Mirati Therapeutics, a novel non-covalent KRAS-G12D inhibitor, MRTX1133, showed significant preclinical antitumor activity in KRAS-G12D-bearing tumor cells, especially pancreatic ductal adenocarcinoma. Here, we discuss the selectivity, efficacy, toxicity, and potential application challenges of this novel targeted protein inhibitor.
AB - KRAS mutations are one of the most common genetic abnormalities in cancer, especially lung, colon, and pancreatic cancers. Strategies targeting the oncogenic KRAS pathway include direct and indirect approaches. KRAS-G12C inhibitors developed based on binding to the switch II pocket structure of KRAS mutant protein represent a breakthrough in the development of targeted therapeutic strategies against oncogenic proteins previously considered undruggable. The covalent KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are used to treat patients with KRAS-G12C-mutated non-small cell lung cancer. Emerging research shows that other host point mutations in KRAS can also be directly targeted by small-molecule compounds. Recently, through extensive structure-based drug design from Mirati Therapeutics, a novel non-covalent KRAS-G12D inhibitor, MRTX1133, showed significant preclinical antitumor activity in KRAS-G12D-bearing tumor cells, especially pancreatic ductal adenocarcinoma. Here, we discuss the selectivity, efficacy, toxicity, and potential application challenges of this novel targeted protein inhibitor.
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U2 - 10.1038/s41417-022-00561-3
DO - 10.1038/s41417-022-00561-3
M3 - Editorial
C2 - 36414681
AN - SCOPUS:85142253387
SN - 0929-1903
VL - 30
SP - 391
EP - 393
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 3
ER -