Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
Drug Development and Innovation Center, College of Chemistry and Life Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China.
Molecules. 2023 Apr 21;28(8):3615. doi: 10.3390/molecules28083615.
KRAS gene mutation is widespread in tumors and plays an important role in various malignancies. Targeting KRAS mutations is regarded as the "holy grail" of targeted cancer therapies. Recently, multiple strategies, including covalent binding strategy, targeted protein degradation strategy, targeting protein and protein interaction strategy, salt bridge strategy, and multivalent strategy, have been adopted to develop KRAS direct inhibitors for anti-cancer therapy. Various KRAS-directed inhibitors have been developed, including the FDA-approved drugs sotorasib and adagrasib, KRAS-G12D inhibitor MRTX1133, and KRAS-G12V inhibitor JAB-23000, etc. The different strategies greatly promote the development of KRAS inhibitors. Herein, the strategies are summarized, which would shed light on the drug discovery for both KRAS and other "undruggable" targets.
KRAS 基因突变广泛存在于肿瘤中，在各种恶性肿瘤中发挥着重要作用。针对 KRAS 突变被视为靶向癌症治疗的“圣杯”。最近，已经采用了多种策略，包括共价结合策略、靶向蛋白降解策略、靶向蛋白与蛋白相互作用策略、盐桥策略和多价策略，来开发用于抗癌治疗的 KRAS 直接抑制剂。已经开发出各种 KRAS 靶向抑制剂，包括 FDA 批准的药物 sotorasib 和 adagrasib、KRAS-G12D 抑制剂 MRTX1133 和 KRAS-G12V 抑制剂 JAB-23000 等。这些不同的策略极大地推动了 KRAS 抑制剂的发展。本文总结了这些策略，这将为 KRAS 及其他“不可成药”靶点的药物发现提供启示。
