Long-term administration of the mutant IDH inhibitor DS-1001b suppresses the growth of IDH1-mutant glioma in vitro and in mouse xenograft models and alters epigenetic profiles.

Heterozygous mutations in isocitrate dehydrogenase (IDH) 1 and 2 are hallmarks of astrocytoma, IDH-mutated, and oligodendroglioma, IDH-mutated, as defined by the World Health Organization Classification of Tumors of the Central Nervous System, 5th Edition. Mutant IDH confers a neomorphic enzymatic activity that converts α-ketoglutarate (α-KG) into the oncometabolite D-2-hydroxyglutarate (D-2-HG), which inhibits α-KG-dependent dioxygenases and induces a global DNA hypermethylation phenotype, also known as Glioma CpG Island Methylator Phenotype (G-CIMP). To elucidate mechanisms underlying the antitumor effects of DS-1001b-a novel, brain-penetrant, orally available inhibitor of mutant IDH1 R132H and R132C-we performed preclinical analyses using IDH1 R132H-mutant glioma cells in vitro and orthotopic mouse xenograft models (MGG152, BT142, and A1074). DS-1001b treatment reduced 2-HG levels in vitro and in vivo and significantly prolonged survival in A1074 and BT142 intracranial xenograft models (p = 0.0064 and 0.0004, respectively), confirming effective target inhibition in the brain. In vitro, prolonged DS-1001b exposure partly reversed genome-wide DNA hypermethylation and revealed that H3K4me3 modulation was mostly associated with differential gene expression, affecting pathways related to apoptosis, necrosis, cell cycle arrest, and migration in MGG152. Metabolomic analyses further demonstrated a significant reduction in asparagine in A1074, consistent with the activation of L-asparaginase-mediated pathways. Collectively, these findings indicate that sustained DS-1001b administration exerts antitumor effects in IDH1-mutant glioma mouse models and induces transcriptomic, epigenetic, and metabolic reprogramming.