新型SOS1抑制剂在kras驱动癌症中的设计和结构优化。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-16 DOI:10.1016/j.bmcl.2025.130282

Yating Chen , Qiupei Liu , Xianghui Meng , Wenxu Cao , Lihui Duo , Xiaorong Song , Xiangchun Shen , Sze Shin Low , Wan Yong Ho , Bencan Tang , Pengli Zhang , Hua Xie , Guoqin Xia

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引用次数: 0

摘要

开发靶向鸟嘌呤核苷酸交换因子SOS1的小分子抑制剂已被证明是治疗各种kras驱动的癌症的一种有希望的策略。由于早期类似物的结构相似性导致耐药性增加，因此迫切需要构建新的SOS1抑制剂。在此，我们发现了一种新的SOS1抑制剂与对二甲氨基氮杂啶喹唑啉支架。在KRASG12C::SOS1 PPI抑制实验和3D增殖抑制实验中，最有效的化合物10i显示出比报道的SOS1抑制剂Hit 1更强的活性，并且化合物10i在生理相关pH 6.8下的水溶性增强。此外，化合物10i可下调NCI-H358癌细胞中磷酸化的ERK和AKT水平。总的来说，这些研究表明10i是治疗kras驱动的癌症的有希望的候选药物。

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Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

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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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.