William McCoull; Scott Boyd; Martin R. Brown; Muireann Coen; Olga Collingwood; Nichola L. Davies; Ann Doherty; Gary Fairley; Kristin Goldberg; Elizabeth Hardaker; Guang He; Edward J. Hennessy; Philip Hopcroft; George Hodgson; Anne Jackson; Xiefeng Jiang; Ankur Karmokar; Anne-Laure Lainé; Nicola Lindsay; Yumeng Mao; Roshini Markandu; Lindsay McMurray; Neville McLean; Lorraine Mooney; Helen Musgrove; J. Willem M. Nissink; Alexander Pflug; Venkatesh Pilla Reddy; Philip B. Rawlins; Emma Rivers; Marianne Schimpl; Graham F. Smith; Sharon Tentarelli; Jon Travers; Robert I. Troup; Josephine Walton; Cheng Wang; Stephen Wilkinson; Beth Williamson; Jon Winter-Holt; Dejian Yang; Yuting Zheng; Qianxiu Zhu; Paul D. Smith
J. Med. Chem., 2021, 64(18), 13524-13539
https://doi.org/10.1021/acs.jmedchem.1c00920

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-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.