Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers.
作者信息
Chen Yating, Liu Qiupei, Meng Xianghui, Cao Wenxu, Duo Lihui, Song Xiaorong, Shen Xiangchun, Low Sze Shin, Ho Wan Yong, Tang Bencan, Zhang Pengli, Xie Hua, Xia Guoqin
机构信息
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550014, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Faculty of Science and Engineering, The University of Nottingham Ningbo China, Ningbo 315100, China.
出版信息
Bioorg Med Chem Lett. 2025 Sep 1;125-126:130282. doi: 10.1016/j.bmcl.2025.130282. Epub 2025 May 16.
The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could downregulate the levels of phosphorylated ERK and AKT in the NCI-H358 cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven cancer.
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