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
  • 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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