Key Laboratory of Marine Drugs, Chinese Ministry of Education; School of Medicine and Pharmacy, Ocean University of China, Qingdao 26003, Shandong, P. R. China.
Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao 266200, P. R. China.
Org Biomol Chem. 2024 Jul 3;22(26):5374-5384. doi: 10.1039/d4ob00694a.
The success of targeted covalent inhibitors (TCIs) for treating cancers has spurred the search for novel scaffolds to install covalent warheads. In our endeavour, using a scaffold hopping strategy, we managed to utilize imidazo[1,2-]pyridine as the core backbone and explored its potential for the development of covalent inhibitors, therefore, synthesizing a series of novel KRAS G12C inhibitors facilitated by the Groebke-Blackburn-Bienaymè reaction (GBB reaction). Preliminary bio-evaluation screening delivered compound I-11 as a potent anticancer agent for KRAS G12C-mutated NCI-H358 cells, whose effects were further clarified by a series of cellular, biochemical, and molecular docking experiments. These results not only indicate the potential of compound I-11 as a lead compound for the treatment of intractable cancers, but also validate the unique role of imidazo[1,2-]pyridine as a novel scaffold suitable for the discovery of covalent anticancer agents.
靶向共价抑制剂 (TCIs) 在癌症治疗方面的成功，促使人们寻找新的支架来安装共价弹头。在我们的努力中，我们使用支架跳跃策略，成功地将咪唑并[1,2-a]吡啶作为核心骨架，并探索了其开发共价抑制剂的潜力，因此，通过 Groebke-Blackburn-Bienaymé 反应 (GBB 反应) 合成了一系列新型 KRAS G12C 抑制剂。初步的生物评价筛选提供了化合物 I-11，作为 KRAS G12C 突变的 NCI-H358 细胞的有效抗癌剂，其作用通过一系列细胞、生化和分子对接实验得到进一步阐明。这些结果不仅表明化合物 I-11 作为治疗难治性癌症的潜在先导化合物的潜力，而且验证了咪唑并[1,2-a]吡啶作为适合发现共价抗癌剂的新型支架的独特作用。
