Discovery of HMPL-306 (Ranosidenib), a New Potentand Selective Dual Inhibitor of Mutant IDH1 and 2 in Clinical Developmentfor Cancer Treatment

Mutations in isocitrate dehydrogenase (IDH) 1 or 2 are identified in various cancers. Accumulated (<i>R</i>)-2-hydroxyglutarate (2-HG) caused by mutant IDHs leads to blockage of cell differentiation, thereby inducing malignant transformation. Herein we describe the medicinal chemistry efforts that discovered novel mutant IDH inhibitor HMPL-306 (ranosidenib) via structure–activity relationship studies and pharmacokinetic optimization from internal hit compound <b>1</b>. HMPL-306 is a potent and selective dual inhibitor of mutant IDH1 and 2. It demonstrated favorable preclinical pharmacokinetics and safety profiles, reduced 2-HG <i>in vivo</i> robustly and sustainably in the mutant IDH1 and 2 tumor xenograft models, and displayed high brain penetration in mice. In the clinical studies, the drug showed good safety and encouraging efficacy in patients with relapsed/refractory myeloid malignancies carrying IDH1 and/or IDH2 mutations.