Sep 2026· Drug Discovery Today· Vol 31, pp.
104797
· 0 citations· 133 references
Medicine
TL;DR
This review classifies mutant IDH inhibitors by chemical scaffold and relates their binding in the allosteric pocket to structure-activity trends, isoform selectivity, brain penetration, and clinical outcome.
Abstract
Isocitrate dehydrogenase (IDH) enzymes convert isocitrate to α-ketoglutarate. When IDH1 or IDH2 is mutated, the enzyme gains a new function, and the oncometabolite D-2-hydroxyglutarate (D-2-HG) accumulates. Its epigenetic and metabolic effects depend on the tumor context. This review classifies mutant IDH inhibitors by chemical scaffold and relates their binding in the allosteric pocket to structure-activity trends, isoform selectivity, brain penetration, and clinical outcome. Mutant IDH1, mutant IDH2, pan-IDH, and covalent inhibitors are compared, with lessons from successful and failed clinical candidates. Resistance is treated separately: secondary mutations, isoform switching, metabolic adaptation, rational combinations, PROTAC degraders, and biomarkers. Since reduced 2-HG indicates target engagement rather than clinical benefit, design priorities for the next generation of IDH-directed agents are outlined.
A covalent fragment-based approach was used to develop IDH1-C269 selective inhibitors which prevent the key regulatory segment from forming an α-helix required for catalytic competency, and provide structurally validated inhibitors for further development.
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