2. Academic Validation
  3. Exploiting structural variability in the kinase back-pocket to modulate polypharmacology of TAM inhibitors

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

  • Eur J Med Chem. 2025 Jun 5:290:117561. doi: 10.1016/j.ejmech.2025.117561.
Megan D Hopkins 1,  Dehui Zhang 1,  Zhilong Chen 1,  Andrew L McIver 1,  Justus M Huelse 2,  Jyoti P Mahajan 1,  Kaikai Lyu 1,  Xiangbo Yang 1,  Michael A Stashko 1,  Brittany Smith 2,  Tsz Y Yeung 2,  H Shelton Earp 3,  Stephen V Frye 4,  Deborah DeRyckere 2,  Dmitri Kireev 1,  Douglas K Graham 2,  Xiaodong Wang 5
Affiliations

Affiliations

  • 1 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.
  • 2 Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 4 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; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 5 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; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: xiaodonw@unc.edu.
PMID: 40184776 DOI: 10.1016/j.ejmech.2025.117561
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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