Identification of novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 by cross docking-based virtual screening. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Zou, Fangxia; Pusch, Stefan; Hua, Jie; Ma, Tianfang; Yang, Lijun; Zhu, Qihua; Xu, Yungen; Gu, Yueqing; von Deimling, Andreas; Zha, Xiaoming
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 3(2018)
• Page Start: 388
• Page End: 393
• Publication Date: 2018-02-01
• Subjects: IDH isocitrate dehydrogenase -- ICT isocitrate acid -- α-KG α-ketoglutaric acid -- D2HG D-2-hydroxyglutaric acid -- mIDH1 mutant IDH1 -- mIDH2 mutant IDH2 -- R132H Arg132 mutation to His -- R132C Arg132 mutation to Cys -- WT wild type -- R140Q Arg140 mutation to Gln; Mutant IDH1 -- Inhibitors -- Docking -- Gliomas -- Allosteric -- BBB; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.12.030
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Cross docking-based Virtual Screening was employed to screen SPECS library, followed by cellular assays of mutant and wild types of IDH1. Abstract: 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. CompoundsZX01, ZX05 andZX06 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) identifiedZX06 with a good ability to penetrate BBB. These findings indicate thatZX06 deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers.