Highlighting the mechanistic role of Olutasidenib (FT-2102) in the selective inhibition of mutated isocitrate dehydrogenase 1 (mIDH1) in cancer therapy

Abstract

Mutations in isocitrate dehydrogenase enzymes 1 and 2 (mIDH1/2) results in an aberrant accumulation of (R)-2-hydroxyglutarate (2-HG), excess of which has been shown to inhibit alpha ketoglutarate (αKG)-dependent enzymes leading to the development of gliomas. Inhibition of mutant IDH1 has therefore been evaluated clinically as a treatment option for gliomas. Recently, Olutasidenib (FT-2102), was discovered as a highly potent and selective inhibitor of mIDH1. However, the mechanistic activities surrounding its selective inhibitory potency remain unclear. Herein, this study provides the structural and mechanistic insights that underpin the reported selectivity of FT-2102 on mDH1 using molecular dynamic (MD) simulations and advanced post-MD analysing techniques. Findings revealed that the selectivity of FT-2102 towards mIDH1 is mediated by high-affinity interactions with residues Arg109, Ile128 and Val281 within the binding pocket. Also, a unidirectional orientation of FT-2102 within mIDH1 anchored by the high-affinity interactions accounted for its higher stability and stronger binding of −56.82 kcal/mol relative to lower binding affinity of −14.48 kcal/mol towards mIDH2. Furthermore, the binding of FT-2102 in mIDH1 conferred more stability at the binding pocket which resulted in maintenance of crucial atomic interactions as compared to mIDH2 where binding was characterized by inconsistency and loss of crucial interactions. These findings thus present a detailed insight into the selective inhibitory mechanism of FT-2102 towards mIDH1 and could aid in the design and development of novel mutant IDH inhibitors.