Hopkins Megan D, Zhang Dehui, Chen Zhilong, McIver Andrew L, Huelse Justus M, Mahajan Jyoti P, Lyu Kaikai, Yang Xiangbo, Stashko Michael A, Smith Brittany, Yeung Tsz Y, Earp H Shelton, Frye Stephen V, DeRyckere Deborah, Kireev Dmitri, Graham Douglas K, Wang Xiaodong
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Eur J Med Chem. 2025 Jun 5;290:117561. doi: 10.1016/j.ejmech.2025.117561. Epub 2025 Mar 28.
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.
酪氨酸激酶受体A（TAM）激酶在肿瘤细胞和先天免疫系统中发挥双重作用。虽然它们具有冗余功能，但在特定情况下对TAM激酶的需求有所不同。因此，在不同的肿瘤类型中，抑制特定的TAM激酶或TAM激酶对将是可取的。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理学，并发现了几种具有不同选择性谱的抑制剂。先导化合物45（UNC8212）对TAM家族显示出强大的抑制活性。通过纳米生物发光共振能量转移（NanoBRET）和基于细胞的试验证实了其与靶点的结合。通过静脉内和腹腔内途径，它还具有良好的药代动力学性质。
