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Discovery of potent and noncovalent KRAS^G12D inhibitors: Structure-based virtual screening and biological evaluation.

ABSTRACT: KRAS^G12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of pancreatic cancer. Herein, we identified four potent and noncovalent KRAS^G12D inhibitors (hits 1-4) by using structure-based virtual screening and biological evaluation. The in vitro assays indicated that the four compounds had sub-nanomolar affinities for KRAS^G12D and showed a dose-dependent inhibitory effect on human pancreatic cancer cells. In particular, the hit compound 3 was the most promising candidate and significantly inhibited the tumor growth of pancreatic cancer in tumor-bearing mice. The hit compound 3 represented a promising starting point for structural optimization in hit-to-lead development. This study shows that hit compound 3 provides a basis for the development of the treatment of cancer driven by KRAS^G12D.

SUBMITTER: Wang Y

PROVIDER: S-EPMC9815544 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Discovery of potent and noncovalent KRASG12D inhibitors: Structure-based virtual screening and biological evaluation.

Wang Yuting Y Zhang Hai H Li Jindong J Niu Miao-Miao MM Zhou Yang Y Qu Yuanqian Y

Frontiers in pharmacology 20221222

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of pancreatic cancer. Herein, we identified four potent and noncovalent KRASG12D inhibitors (hits 1-4) by using structure-based virtual screening and biological evaluation. The in vitro assays indicated that the four compounds had sub-nanomolar affinities for KRASG12D and showed a dose-dependent inhibitory effect on human pancreatic cancer cells. In particular, the h ...[more]

PMID: 36618907

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