2. Academic Validation
  3. 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.
PMID: 34478292 DOI: 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.

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