Identification of novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 by cross docking-based virtual screening

被引:15
|
作者
Zou, Fangxia [1 ,2 ,3 ]
Pusch, Stefan [5 ,6 ]
Hua, Jie [4 ]
Ma, Tianfang [1 ,2 ,3 ]
Yang, Lijun [1 ,2 ]
Zhu, Qihua [3 ]
Xu, Yungen [3 ]
Gu, Yueqing [1 ,2 ]
von Deimling, Andreas [5 ,6 ]
Zha, Xiaoming [1 ,2 ]
机构
[1] China Pharmaceut Univ, Sch Engn, Dept Pharmaceut Engn, 539 Longmian Ave, Nanjing 211198, Jiangsu, Peoples R China
[2] China Pharmaceut Univ, Sch Engn, Dept Biochem Engn, 539 Longmian Ave, Nanjing 211198, Jiangsu, Peoples R China
[3] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China
[4] Nanjing Med Univ, Affliated Hosp 1, Dept Gastroenterol, 300 Guangzhou Rd, Nanjing 210029, Jiangsu, Peoples R China
[5] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, German Consortium Translat Canc Res DKTK, INF 280, D-69120 Heidelberg, Germany
[6] Ruprecht Karls Univ Heidelberg, Inst Pathol, Dept Neuropathol, INF 224, D-69120 Heidelberg, Germany
关键词
Mutant IDH1; Inhibitors; Docking; Gliomas; Allosteric; BBB; SELECTIVE-INHIBITION; IDH MUTATIONS; DIFFERENTIATION; LEUKEMIA; CANCER;
D O I
10.1016/j.bmcl.2017.12.030
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
IDH1 mutation (mIDH1) occurs in 20-30% of gliomas and is a promising target for the cancer therapy. In this article, a cross docking-based virtual screening was employed to identify seven small molecules for the allosteric site of mIDH1. Compounds ZX01, ZX05 and ZX06 exhibited the potent inhibitory activity and the high selectivity against WT-IDH1, providing a good starting point for the further development of highly selective mIDH1 inhibitors. Importantly, the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified ZX06 with a good ability to penetrate BBB. These findings indicate that ZX06 deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码:388 / 393
页数:6
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