Mr. Jinjie Song Profile

Jinjie Song

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Proceedings Article | 8 January 2024 Paper

Targeting KRAS G12C: progress made and promise ahead

Huiqi Dai, Shuang Fang, Jinjie Song

Proceedings Volume 12924, 129243Z (2024) https://doi.org/10.1117/12.3013204

KEYWORDS: Tumors, Proteins, Switches, Molecules, Cancer, Nickel, Design and modelling, Chemistry, Error control coding, Cell death

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KRAS oncogenic mutations are existent in 15% of human malignancies, resulting in constitutive activation of KRAS. Prior attempts failed to target this protein leading to the claim that KRAS was undruggable. However, the disclosure of a new allosteric pocket on KRASG12C substantially empowers anti-KRAS drug design and represents an amazing breakthrough made by structural biology and medicinal chemistry efforts. AMG510 and MRTX849 are remarkable in the design of G12C covalent inhibitors and have shown encouraging results clinically, with several more anti-cancer therapeutic drugs targeting KRASG12C on the horizon. Herein we provide a brief review of the structure of KRAS, its function and KRAS-related pathway, and its common mutations in human tumors, especially KRASG12C. Then, we discuss the most recent advancements in developing KRASG12C covalent inhibitors, as well as their chemical structures as well as the challenging but promising future of new development and translational applications of KRASG12C inhibitor to improve human health.

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