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.

Autor:	McCoull W; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Boyd S; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Brown MR; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Coen M; Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Collingwood O; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Davies NL; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Doherty A; Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Fairley G; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Goldberg K; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Hardaker E; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., He G; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China., Hennessy EJ; Oncology R&D, AstraZeneca, Gatehouse Park, Waltham, Massachusetts 02451, United States., Hopcroft P; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Hodgson G; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Jackson A; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Jiang X; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China., Karmokar A; Oncology R&D, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Lainé AL; Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Lindsay N; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Mao Y; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Markandu R; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., McMurray L; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., McLean N; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Mooney L; Oncology R&D, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Musgrove H; Oncology R&D, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Nissink JWM; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Pflug A; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Reddy VP; Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Rawlins PB; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Rivers E; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Schimpl M; Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Smith GF; Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Tentarelli S; Oncology R&D, AstraZeneca, Gatehouse Park, Waltham, Massachusetts 02451, United States., Travers J; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Troup RI; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Walton J; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Wang C; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China., Wilkinson S; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Williamson B; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Winter-Holt J; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K., Yang D; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China., Zheng Y; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China., Zhu Q; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China., Smith PD; Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Sep 23; Vol. 64 (18), pp. 13524-13539. Date of Electronic Publication: 2021 Sep 03.
DOI:	10.1021/acs.jmedchem.1c00920
Abstrakt:	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.
Databáze:	MEDLINE
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