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

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2025-02-13 eCollection Date: 2025-03-13 DOI:10.1021/acsmedchemlett.4c00625

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

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Abstract

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.

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HMPL-306 （Ranosidenib）的发现，一种新的有效和选择性的突变体IDH1和2的双重抑制剂在癌症治疗的临床开发中。

异柠檬酸脱氢酶（IDH） 1或2的突变在各种癌症中被发现。突变IDHs引起的(R)-2-羟基戊二酸（2-HG）的积累导致细胞分化受阻，从而诱发恶性转化。在此，我们描述了药物化学方面的努力，通过对内参化合物1的构效关系研究和药代动力学优化，发现了新的突变型IDH抑制剂HMPL-306 （ranosidenib）。HMPL-306是一种有效的、选择性的IDH1和2突变体双重抑制剂。它显示出良好的临床前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稳定和持续地降低体内2- hg，并在小鼠中表现出高的脑穿透性。在临床研究中，该药对携带IDH1和/或IDH2突变的复发/难治性髓系恶性肿瘤患者显示出良好的安全性和令人鼓舞的疗效。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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