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

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

  • J Med Chem. 2021 Sep 23;64(18):13524-13539. doi: 10.1021/acs.jmedchem.1c00920.
William McCoull 1 Scott Boyd 1 Martin R Brown 2 Muireann Coen 3 Olga Collingwood 1 Nichola L Davies 1 Ann Doherty 3 Gary Fairley 1 Kristin Goldberg 1 Elizabeth Hardaker 1 Guang He 4 Edward J Hennessy 5 Philip Hopcroft 2 George Hodgson 2 Anne Jackson 2 Xiefeng Jiang 4 Ankur Karmokar 6 Anne-Laure Lainé 7 Nicola Lindsay 1 Yumeng Mao 1 Roshini Markandu 1 Lindsay McMurray 1 Neville McLean 1 Lorraine Mooney 6 Helen Musgrove 6 J Willem M Nissink 1 Alexander Pflug 2 Venkatesh Pilla Reddy 3 Philip B Rawlins 2 Emma Rivers 2 Marianne Schimpl 2 Graham F Smith 3 Sharon Tentarelli 5 Jon Travers 1 Robert I Troup 1 Josephine Walton 1 Cheng Wang 4 Stephen Wilkinson 1 Beth Williamson 1 Jon Winter-Holt 1 Dejian Yang 4 Yuting Zheng 4 Qianxiu Zhu 4 Paul D Smith 1
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 2 Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 3 Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 4 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China.
  • 5 Oncology R&D, AstraZeneca, Gatehouse Park, Waltham, Massachusetts 02451, United States.
  • 6 Oncology R&D, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
  • 7 Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
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.

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