Xiao Kun, Zhang Zheng, Wu Yao, Li Gang, Chen Jia, Ren Yongxin, Yang Na, Zhou Jinghong, Zhang Wei, Wang Jian, Zhong Zeyu, Xia Sumei, Wang Guanglin, Li Na, Li Wenji, Feng Ling, Zhang Weihan, Su Weiguo, Dai Guangxiu
HUTCHMED Limited, Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, 201203 Shanghai, China.
ACS Med Chem Lett. 2025 Feb 13;16(3):454-463. doi: 10.1021/acsmedchemlett.4c00625. eCollection 2025 Mar 13.
Mutations in isocitrate dehydrogenase (IDH) 1 or 2 are identified in various cancers. Accumulated ()-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 . 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 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.
异柠檬酸脱氢酶（IDH）1或2的突变在多种癌症中被发现。突变型IDH导致的（R）-2-羟基戊二酸（2-HG）积累会导致细胞分化受阻，从而诱导恶性转化。在此，我们描述了药物化学方面的工作，即通过构效关系研究和对内部活性化合物进行药代动力学优化，发现了新型突变型IDH抑制剂HMPL-306（ivosidenib）。HMPL-306是一种强效且选择性的突变型IDH1和2双重抑制剂。它在临床前显示出良好的药代动力学和安全性，在突变型IDH1和2肿瘤异种移植模型中能强劲且持续地降低2-HG水平，并且在小鼠体内表现出高脑渗透性。在临床研究中，该药物在携带IDH1和/或IDH2突变的复发/难治性髓系恶性肿瘤患者中显示出良好的安全性和令人鼓舞的疗效。
