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

作者：Kun Xiao, Zheng Zhang, Yao Wu, Gang Li, Jia Chen, Yongxin Ren, Na Yang, Jinghong Zhou, Wei Zhang, Jian Wang, Zeyu Zhong, Sumei Xia, Guanglin Wang, Na Li, Wenji Li, Ling Feng, Weihan Zhang, Weiguo Su, Guangxiu Dai · 发表于：ACS Medicinal Chemistry Letters · 年份：2025 · DOI：10.1021/acsmedchemlett.4c00625 · 被引用次数：8 · 研究领域：Histone Deacetylase Inhibitors Research、Protein Degradation and Inhibitors、Cancer Mechanisms and Therapy

Mutations in isocitrate dehydrogenase (IDH) 1 or 2 are identified in various cancers. Accumulated ( R )-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 1 . 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 in vivo 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.