Discovery of new small molecule inhibitors targeting isocitrate dehydrogenase 1 (IDH1) with blood-brain barrier penetration

Hengyi Cao; Guangya Zhu; Lin Sun; Ge Chen; Xinxin Ma; Xiao Luo; Jidong Zhu

doi:10.1016/j.ejmech.2019.111694

Discovery of new small molecule inhibitors targeting isocitrate dehydrogenase 1 (IDH1) with blood-brain barrier penetration

Eur J Med Chem. 2019 Dec 1:183:111694. doi: 10.1016/j.ejmech.2019.111694. Epub 2019 Sep 13.

Authors

Hengyi Cao¹, Guangya Zhu¹, Lin Sun², Ge Chen², Xinxin Ma², Xiao Luo², Jidong Zhu³

Affiliations

¹ Interdisciplinary Research Center on Biology and Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201203, China; University of the Chinese Academy of Sciences, Beijing, 100049, China.
² Interdisciplinary Research Center on Biology and Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201203, China.
³ Interdisciplinary Research Center on Biology and Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: zhujd@sioc.ac.cn.

PMID: 31561044
DOI: 10.1016/j.ejmech.2019.111694

Abstract

Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg¹³² in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5 exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclinical candidate to treat IDH1-mutant brain tumors.

Keywords: Acute myeloid leukemia; Blood-brain barrier; Cancer therapy; Glioblastoma; Isocitrate dehydrogenase 1; Small molecule inhibitors.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Blood-Brain Barrier / drug effects*
Blood-Brain Barrier / metabolism
Brain Neoplasms / drug therapy*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Female
Glioma / drug therapy*
Glioma / metabolism
Glioma / pathology
Humans
Isocitrate Dehydrogenase / antagonists & inhibitors*
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Small Molecule Libraries
Isocitrate Dehydrogenase
IDH1 protein, human