European journal of medicinal chemistry · 2025
Exploiting structural variability in the kinase back-pocket to modulate polypharmacology of TAM inhibitors.
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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
Аннотация
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.