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Discovery of new small molecule inhibitors targeting isocitrate dehydrogenase 1 (IDH1) with blood-brain barrier penetration.
- Source :
-
European Journal of Medicinal Chemistry . Dec2019, Vol. 183, pN.PAG-N.PAG. 1p. - Publication Year :
- 2019
-
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. 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]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 183
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 139436958
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.111694