Structure-based design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain pene-trant and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in a mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hemato-logic malignancies, solid tumors, and gliomas with mIDH1.