Structure-Based Design of Potent and Selective MerTK Inhibitors by Modulating the Conformation of αC Helix

J Med Chem. 2025 Jun 12;68(11):10877-10896. doi: 10.1021/acs.jmedchem.4c03092. Epub 2025 May 20.

Abstract

Tumor-associated macrophages play an important role in cancer progression and immunosuppression, making their receptors promising therapeutic targets. MerTK, a TAM receptor, regulates macrophage efferocytosis and polarization, and its inhibition holds potential for tumor growth suppression and immune modulation. However, Tyro3, another TAM receptor, is involved in neurogenesis, highlighting the need to selectively target MerTK while avoiding Tyro3 inhibition to prevent neurotoxicity. In this study, we present a novel strategy for designing MerTK-selective inhibitors by modulating the conformational dynamics of its αC helix. By integrating structural biology, medicinal chemistry, protein stabilization assays, and molecular docking studies, we identified compound 11, which demonstrates potent inhibition and selectivity for MerTK. Pharmacokinetic evaluations and in vivo studies further reveal compound 11 as a promising candidate for further development. Our findings not only advance the understanding of the MerTK-specific mechanism but also propose a strategy for designing selective kinase inhibitors targeting the αC helix conformation.

MeSH terms

  • Animals
  • Drug Design*
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Protein Conformation, alpha-Helical / drug effects
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / metabolism
  • Protein Kinase Inhibitors* / pharmacokinetics
  • Protein Kinase Inhibitors* / pharmacology
  • Structure-Activity Relationship
  • c-Mer Tyrosine Kinase* / antagonists & inhibitors
  • c-Mer Tyrosine Kinase* / chemistry
  • c-Mer Tyrosine Kinase* / metabolism

Substances

  • c-Mer Tyrosine Kinase
  • Protein Kinase Inhibitors
  • MERTK protein, human