作为TRK抑制剂的吡唑并[3,4 - ]吡啶衍生物的设计、合成及生物学评价
Design, synthesis and biological evaluation of pyrazolo[3,4-]pyridine derivatives as TRK inhibitors.
作者信息
Liu Nian, Wang Xin, Fu Qinglin, Qin Qiaohua, Wu Tianxiao, Lv Ruicheng, Zhao Dongmei, Cheng Maosheng
机构信息
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District Shenyang 110016 PR China.
出版信息
RSC Med Chem. 2022 Oct 18;14(1):85-102. doi: 10.1039/d2md00334a. eCollection 2023 Jan 25.
Abstract
Tropomyosin receptor kinases (TRKs) are associated with the proliferation and differentiation of cells, and thus their continuous activation and overexpression cause cancer. Herein, based on scaffold hopping and computer-aid drug design, 38 pyrazolo[3,4-]pyridine derivatives were synthesised. Further, we evaluated their activities to inhibit TRKA. Among them, compound C03 showed acceptable activity with an IC value of 56 nM and it inhibited the proliferation of the Km-12 cell line with an IC value of 0.304 μM together with obvious selectivity for the MCF-7 cell line and HUVEC cell line. Furthermore, compound C03 possessed good plasma stability and low inhibitory activity to a panel of cytochrome P450 isoforms except CYP2C9. Overall, C03 has potential for further exploration.
摘要
原肌球蛋白受体激酶（TRKs）与细胞的增殖和分化相关，因此它们的持续激活和过表达会引发癌症。在此，基于骨架跃迁和计算机辅助药物设计，合成了38种吡唑并[3,4 - ]吡啶衍生物。此外，我们评估了它们抑制TRKA的活性。其中，化合物C03表现出可接受的活性，IC值为56 nM，它以0.304 μM的IC值抑制Km - 12细胞系的增殖，同时对MCF - 7细胞系和HUVEC细胞系具有明显的选择性。此外，化合物C03具有良好的血浆稳定性，并且对除CYP2C9之外的一组细胞色素P450同工酶具有低抑制活性。总体而言，C03具有进一步探索的潜力。
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