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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

DOI: 10.1021/acs.jmedchem.1c00920 DOI Help

Authors: William Mccoull (AstraZeneca) , Scott Boyd (AstraZeneca) , Martin R. Brown (AstraZeneca) , Muireann Coen (AstraZeneca) , Olga Collingwood (AstraZeneca) , Nichola L. Davies (AstraZeneca) , Ann Doherty (AstraZeneca) , Gary Fairley (AstraZeneca) , Kristin Goldberg (AstraZeneca) , Elizabeth Hardaker (AstraZeneca) , Guang He (Pharmaron Beijing Co., Ltd) , Edward J. Hennessy (AstraZeneca) , Philip Hopcroft (AstraZeneca) , George Hodgson (AstraZeneca) , Anne Jackson (AstraZeneca) , Xiefeng Jiang (Pharmaron Beijing Co., Ltd) , Ankur Karmokar (AstraZeneca) , Anne-Laure Lainé (AstraZeneca) , Nicola Lindsay (AstraZeneca) , Yumeng Mao (AstraZeneca) , Roshini Markandu (AstraZeneca) , Lindsay Mcmurray (AstraZeneca) , Neville Mclean (AstraZeneca) , Lorraine Mooney (AstraZeneca) , Helen Musgrove (AstraZeneca) , J. Willem M. Nissink (AstraZeneca) , Alexander Pflug (AstraZeneca) , Venkatesh Pilla Reddy (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , Emma Rivers (AstraZeneca) , Marianne Schimpl (AstraZeneca) , Graham F. Smith (AstraZeneca) , Sharon Tentarelli (AstraZeneca) , Jon Travers (AstraZeneca) , Robert I. Troup (AstraZeneca) , Josephine Walton (AstraZeneca) , Cheng Wang (Pharmaron Beijing Co., Ltd) , Stephen Wilkinson (AstraZeneca) , Beth Williamson (AstraZeneca) , Jon Winter-Holt (AstraZeneca) , Dejian Yang (Pharmaron Beijing Co., Ltd) , Yuting Zheng (Pharmaron Beijing Co., Ltd) , Qianxiu Zhu (Pharmaron Beijing Co., Ltd) , Paul D. Smith (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 17180

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.

Journal Keywords: Peptides and proteins; Substituents; Inhibition; MERS; Tumors

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 20/09/2021 13:40


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)