KRAS is the most frequently mutated oncogene and drives the development and progression of malignancies, most notably non-small cell lung cancer (NSCLS), pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). However, KRAS proteins have maintained the reputation of being “undruggable” due to the lack of suitable deep pockets on its surface. One major milestone for KRAS inhibition was the discovery of the covalent inhibitors bond to the allosteric switch-II pocket of the KRAS^G12C protein. To date, the FDA has approved two KRAS^G12C inhibitors, sotorasib and adagrasib, for the treatment of patients with KRAS^G12C-driven cancers. Researchers have paid close attention to the development of inhibitors for other KRAS mutations and upstream regulatory factors. The KRAS targeted drug discovery has entered a state of rapid development. This article has aimed to present the current state of the art of drug development in the KRAS field. We systematically summarize recent advances in the discovery and optimization processes of direct KRAS inhibitors (including KRAS^G12C, KRAS^G12D, KRAS^G12A and KRAS^G12R inhibitors), indirect KRAS inhibitors (SOS1 and SHP2 inhibitors), pan-KRAS inhibitors, as well as proteolysis-targeting chimeras degrades and molecular chaperone modulators from the perspective of medicinal chemistry. We also discuss the current challenges and opportunities of KRAS inhibition and hope to shed light on future KRAS drug discovery.

KRAS 是最常见突变的癌基因，可驱动恶性肿瘤的发生和进展，尤其是非小细胞肺癌 (NSCLS)、胰腺导管腺癌(PDAC) 和结直肠癌 (CRC)。然而，KRAS 蛋白由于其表面缺乏合适的深袋，一直保持着“不可成药”的声誉。KRAS 抑制的一个重要里程碑是发现了与 KRAS ^G12C蛋白的变构开关 II 口袋结合的共价抑制剂。迄今为止，FDA 已批准两种 KRAS^G12C抑制剂 sotorasib 和 adagrasib 用于治疗 KRAS^G12C驱动的癌症患者。研究人员密切关注其他 KRAS 突变和上游调控因子的抑制剂的开发。KRAS靶向药物发现已进入快速发展状态。本文旨在介绍 KRAS 领域药物开发的最新技术水平。我们系统总结了直接KRAS抑制剂（包括KRAS ^G12C、KRAS^G12D、KRAS^G12A和KRAS^G12R抑制剂）、间接KRAS抑制剂（SOS1和SHP2抑制剂）、泛KRAS抑制剂以及蛋白水解的药物化学的角度靶向我们还讨论了 KRAS 抑制当前的挑战和机遇，并希望为未来 KRAS 药物的发现提供启示。