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

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. Image 1 • A series of 24 new mutant IDH1 inhibitors have been synthesized and tested. • Compound 5 exhibits excellent inhibitory activity both in the enzyme and in cells. • Compound 5 is demonstrated good pharmacodynamics and pharmacokinetics properties. • Compound 5 exhibits higher exposure than AG-120 in the brain and tumor. • Compound 5 is effective in inhibiting 2-HG in HT1080 xenograft tumor samples. [ABSTRACT FROM AUTHOR]