Exploiting structural variability in the kinase back-pocket to modulate polypharmacology of TAM inhibitors

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI:10.1016/j.ejmech.2025.117561

Megan D. Hopkins , Dehui Zhang , Zhilong Chen , Andrew L. McIver , Justus M. Huelse , Jyoti P. Mahajan , Kaikai Lyu , Xiangbo Yang , Michael A. Stashko , Brittany Smith , Tsz Y. Yeung , H. Shelton Earp , Stephen V. Frye , Deborah DeRyckere , Dmitri Kireev , Douglas K. Graham , Xiaodong Wang

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引用次数: 0

Abstract

TAM kinases play dual roles in tumor cells and the innate immune system. While they have redundant functions, the TAM kinases are differentially required in specific contexts. Therefore, inhibition of specific TAM kinases or pairs of TAM kinases will be desirable in different tumor types. We exploited the relatively more diversified back pocket of TAM kinases to modulate the polypharmacology of small molecule inhibitors and discovered several inhibitors with distinct selectivity profiles. The lead compound 45 (UNC8212) displayed potent inhibitory activities toward the TAM family. Its target engagement was confirmed by NanoBRET and cell-based assays. It also had favorable pharmacokinetic properties via intravenous and intraperitoneal routes.

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TAM 激酶在肿瘤细胞和先天免疫系统中发挥着双重作用。虽然它们具有冗余功能，但在特定情况下对 TAM 激酶的需求不同。因此，在不同的肿瘤类型中，抑制特定的 TAM 激酶或 TAM 激酶对是可取的。我们利用 TAM 激酶相对更多样化的后口袋来调节小分子抑制剂的多药性，发现了几种具有独特选择性的抑制剂。先导化合物 45（UNC8212）显示出对 TAM 家族的强效抑制活性。NanoBRET 和基于细胞的检测证实了其靶向参与性。通过静脉注射和腹腔注射，它还具有良好的药代动力学特性。

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

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.