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Updated: May 16, 2025

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Exploiting structural variability in the kinase back-pocket to modulate polypharmacology of TAM inhibitors
Megan D Hopkins1, Dehui Zhang1, Zhilong Chen1
1Center 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.
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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