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.

Products