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

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.