Roles of metal ions in the selective inhibition of oncogenic variants of isocitrate dehydrogenase 1.

ABSTRACT: Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a 'gain-of-function' to reduce 2-oxoglutarate to 2-hydroxyglutarate. High-throughput screens have enabled clinically useful R132H IDH1 inhibitors, mostly allosteric binders at the dimer interface. We report investigations on roles of divalent metal ions in IDH substrate and inhibitor binding that rationalise this observation. Mg²⁺/Mn²⁺ ions enhance substrate binding to wt IDH1 and R132H IDH1, but with the former manifesting lower Mg²⁺/Mn²⁺ K_Ms. The isocitrate-Mg²⁺ complex is the preferred wt IDH1 substrate; with R132H IDH1, separate and weaker binding of 2-oxoglutarate and Mg²⁺ is preferred. Binding of R132H IDH1 inhibitors at th

SUBMITTER: Liu S 

PROVIDER: S-EPMC8560763 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature