posted on 2021-09-03, 18:04authored byWilliam 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
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.