通过 DNA 编码库技术发现首个选择性小分子 GFRα2/3 抑制剂。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-07-14 DOI:10.1016/j.bmcl.2024.129889

Shea L. Johnson, Galen Missig, Minghua Wang, Kosalvisal Ouk, Kushali Gupta, Hanh Nho Nguyen, May Fern Toh, Tammy Szu-Yu Ho, David Gray, Hongjun Zhang, Yong Mi Choi-Sledeski, Claude Barberis, David J. Stone, Sokhom Pin, Jongwon Lim

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引用次数: 0

摘要

研究表明，破坏配体-RET-GFRα复合物的形成可能是治疗疼痛和瘙痒的有效方法。与传统的高通量筛选相比，DNA编码文库（DEL）近年来已成为一种强大的靶点鉴定技术。本研究利用 DEL 技术确认了化合物 16，它是第一个对 RET 具有选择性的 GFRa2/GFRa3 小分子抑制剂（分别为 0.1/0.2 μM）。该分子为推动以 GFRα-RET 界面为靶点的小分子抑制剂的开发提供了机会，可用于疼痛和瘙痒的治疗。

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Discovery of the first selective, small-molecule GFRα2/3 inhibitors through DNA-encoded library technology

Studies have shown that disrupting the formation of the ligand-RET-GFRα complex could be an effective way of treating pain and itch. Compared to traditional high-throughput screens, DNA encoded libraries (DELs) have distinguished themselves as a powerful technology for hit identification in recent years. The present work demonstrates the use of DEL technology identifying compound 16 as the first GFRa2/GFRa3 small molecule inhibitor (0.1/0.2 μM respectively) selective over RET. This molecule represents an opportunity to advance the development of small-molecule inhibitors targeting the GFRα-RET interface for the treatment of pain and itch.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.