European Journal of Medicinal Chemistry (2020)
Update date:2022-08-29
Topics:
Che, Jinxin
Chen, Binhui
Dong, Xiaowu
Gao, Anhui
Gao, Jian
Hu, Xiaobei
Hu, Yongzhou
Huang, Feng
Li, Jia
Qu, Bingxue
Xu, Gaoya
Ying, Huazhou
Zhang, Jianjun
Zhang, Mengmeng
Zhou, Yubo
The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2R140Q after computational docking and dynamic simulation, which may serve as a good starting point for further development.
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