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. 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.
Keywords:
Allosteric; BBB; Docking; Gliomas; Inhibitors; Mutant IDH1.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Allosteric Site / drug effects
-
Blood-Brain Barrier / drug effects
-
Brain Neoplasms / drug therapy*
-
Brain Neoplasms / metabolism
-
Brain Neoplasms / pathology
-
Dose-Response Relationship, Drug
-
Drug Evaluation, Preclinical
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Glioma / drug therapy*
-
Glioma / metabolism
-
Glioma / pathology
-
HEK293 Cells
-
Humans
-
Isocitrate Dehydrogenase / antagonists & inhibitors*
-
Isocitrate Dehydrogenase / genetics
-
Isocitrate Dehydrogenase / metabolism
-
Molecular Docking Simulation
-
Molecular Structure
-
Mutation
-
Small Molecule Libraries / chemical synthesis
-
Small Molecule Libraries / chemistry
-
Small Molecule Libraries / pharmacology*
-
Structure-Activity Relationship
Substances
-
Enzyme Inhibitors
-
Small Molecule Libraries
-
Isocitrate Dehydrogenase
-
IDH1 protein, human