European Journal of Medicinal Chemistry p. 470 - 482 (2019)
Update date:2022-08-30
Topics:
Cui, Shengyang
Wang, Yongjin
Wang, Yuting
Tang, Xia
Ren, Xiaomei
Zhang, Lei
Xu, Yong
Zhang, Zhang
Zhang, Zhi-Min
Lu, Xiaoyun
Ding, Ke
A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.
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