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.
- 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.
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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Cat. No.Product NameDescriptionTargetResearch Area
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target: TAM ReceptorResearch Areas: Cancer