发现有效的FGFR2/3抑制剂克服突变抵抗和治疗软骨发育不全。

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00294

Donglin Fu, Tian Han, Zimo Yang, Yuanfeng Xia, Zhilong Hu, Fanglong Yang, Siqi Wang, Lei Jin

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引用次数: 0

摘要

软骨发育不全（ACH）是人类侏儒症最常见的形式，大约99%的病例是由FGFR3中的G380R突变引起的。通过Tyra-300和LY2874455的结构杂交，我们开发了化合物23，这是一种新的双靶点FGFR2/3抑制剂，对野生型和突变型FGFR3都有有效的活性。在临床前ACH小鼠模型中，化合物23显示出剂量依赖性的生长速度改善，与同等剂量的发炎替尼相比，其疗效显著增强。这项工作提出了一种新的结构支架，用于开发靶向致病性FGFR3突变的FGFR3激酶抑制剂并治疗ACH。

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Discovery of Potent FGFR2/3 Inhibitors to Overcome Mutation Resistance and Treat Achondroplasia.

Achondroplasia (ACH), the most prevalent form of human dwarfism, is caused by the G380R mutation in FGFR3 in approximately 99% of cases. Through structural hybridization of Tyra-300 and LY2874455, we developed compound 23, a new dual-target FGFR2/3 inhibitor demonstrating potent activity against both wild-type and mutant FGFR3. In preclinical ACH mouse models, compound 23 showed a dose-dependent improvement in growth rate, with significantly enhanced efficacy versus infigratinib at equivalent doses. This work presents a new structural scaffold for developing FGFR3 kinase inhibitors to target pathogenic FGFR3 mutations and treat ACH.

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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.