Background: R132H mutation of isocitrate dehydrogenase 1 (IDH1) is found in ~75%
of low-grade gliomas and secondary glioblastomas as well as in several other types of cancer.
More chemotypes of inhibitors of IDH1(R132H) are therefore needed.
Objective: The study aimed to develop a new class of IDH1(R132H) inhibitors as potent antitumor
Method: A biochemical assay was developed to find inhibitors of IDH1(R132H) mutant enzyme.
Chemical synthesis and structure-activity relationship studies were used to find compounds with
improved potency. Antitumor activities of selected compounds were evaluated.
Results: A series of aromatic sulfonamide compounds was found to be novel, potent inhibitors of
IDH1(R132H) with Ki values as low as 0.6 µM. Structure-activity relationships of these compounds
are discussed. Enzyme kinetics studies showed that one compound is a competitive inhibitor
against the substrate α-KG and a non-competitive inhibitor against the cofactor NADPH. Several
inhibitors were found to have no activity against wild-type IDH1, showing a high selectivity.
Two potent inhibitors exhibited strong activity against proliferation of BT142 glioma cells with
IDH1 R132H mutation, while these compounds did not significantly affect the growth of glioma
cells without IDH1 mutation.
Conclusion: This novel series of IDH1(R132H) inhibitors have potential to be further developed
for the treatment of glioma with IDH1 mutation.