wt-IDH1i-13

wt-IDH1i-13 is a first-in-class, brain-penetrant small molecule inhibitor of wild-type isocitrate dehydrogenase 1 (wt-IDH1), developed by AbbVie. Unlike common IDH inhibitors that target mutant forms (mIDH1), this compound specifically targets the wild-type enzyme, which is often upregulated in high-grade gliomas (HGG) to support de novo lipogenesis and antioxidant defense via NADPH production. wt-IDH1i-13 acts as a competitive α,β-unsaturated enone that covalently binds to the NADP+ binding pocket of wt-IDH1. By inhibiting wt-IDH1, the drug depletes cytosolic NADPH and glutathione (GSH) levels, leading to increased reactive oxygen species (ROS) and the accumulation of polyunsaturated fatty acid (PUFA)-containing lipid peroxides. This biochemical shift induces ferroptotic cell death in glioblastoma cells. Preclinical studies have demonstrated that wt-IDH1i-13 can slow tumor progression and extend survival in mouse models of wt-IDH1-high HGG, both as a monotherapy and in combination with radiation therapy.