Optimization of an Imidazo[1,2-<i>a</i>]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors with <i>In Vivo</i> Efficacy

Abstract

Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-<i>a</i>]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective <i>in vivo</i> probe compound <b>32</b>. We demonstrated dose-dependent <i>in vivo</i> efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, <i>in vivo</i> efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.