Discovery of PF-07054894, a Potent Squaramide-Based CCR6 Antagonist Displaying High CXCR2 Selectivity.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-22 DOI:10.1021/acs.jmedchem.5c01946

Mark E Schnute,Huixian Wu,John I Trujillo,Wei Li,David Jonathan Wasilko,Jennifer Alley,Eric P Arnold,Scott W Bagley,Gabriel Berstein,David C Blakemore,Mark W Bundesmann,Gary M Chinigo,Chulho Choi,Robert Cooke,Kimberly Crouse,Alpay Dermenci,Theresa Dickinson,Andrew Flick,Richard K Frisbie,Carmen Garcia-Irizarry,Brian S Gerstenberger,David Hepworth,Neelu Kaila,Daniel W Kung,Daniel Lamb,Sophie Y Lavergne,David C Limburg,Shenping Liu,Vincent M Lombardo,Prolay K Mondal,James J Mousseau,Arjun Narayanan,Nootaree Niljianskul,Philippe Nuhant,Senliang Pan,Michael J Primiano,Mathieu Rappas,Daniel C Schmitt,Stefanus J Steyn,Ray Unwalla,Dipy Vasa,Michael L Vazquez,Fabien Vincent,Xiaojing Yang,Atli Thorarensen

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引用次数: 0

Abstract

The G protein-coupled receptor (GPCR) CCR6 mediates the migration of pathogenic immune cells to the site of inflammation in response to the chemokine CCL20. CCR6 is an attractive target for the treatment of chronic autoimmune disease as antagonism of the receptor is expected to block CCL20-mediated immune cell recruitment. High-throughput-screening identified a squaramide-based, allosteric antagonist of CCR6 that potently inhibited CCL20-mediated T cell chemotaxis, but it also inhibited CXCL1-mediated neutrophil chemotaxis through CXCR2 antagonism. Lead optimization achieved differentiation from CXCR2 through identification of a methyl substituent-dependent selectivity switch or "magic methyl for selectivity". The mechanism for this effect is rooted in different antagonist-induced ligand-receptor behaviors, insurmountable for CCR6 and surmountable for CXCR2. Herein, we report the discovery and preclinical evaluation of the CCR6 antagonist PF-07054894 (18l) which has advanced to clinical trials as a first in class approach targeting the receptor.

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发现一种有效的基于角鲨酰胺的CCR6拮抗剂PF-07054894，具有高CXCR2选择性。

G蛋白偶联受体（GPCR） CCR6在趋化因子CCL20的作用下介导致病性免疫细胞向炎症部位的迁移。CCR6是治疗慢性自身免疫性疾病的一个有吸引力的靶点，因为该受体的拮抗作用有望阻断ccl20介导的免疫细胞募集。高通量筛选鉴定出一种基于角鲨酰胺的CCR6变构拮抗剂，它能有效抑制ccl20介导的T细胞趋化性，但也能通过CXCR2拮抗剂抑制cxcl1介导的中性粒细胞趋化性。通过鉴定甲基取代基依赖的选择性开关或“选择性神奇甲基”，先导物优化实现了与CXCR2的区别。这种作用的机制源于不同的拮抗剂诱导的配体受体行为，CCR6无法克服，CXCR2可以克服。在此，我们报告了CCR6拮抗剂PF-07054894 （18l）的发现和临床前评估，该拮抗剂已作为靶向受体的同类方法进入临床试验。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.