Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In Vivo Target Engagement.

Autor:	Frey RR; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Jana N; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Gorman JV; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Wang J; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Smith HA; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Bromberg KD; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Thakur A; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Doktor SZ; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Indulkar AS; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Jakob CG; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Upadhyay AK; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Qiu W; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Manaves V; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Gambino F Jr; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Valentino SA; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Montgomery D; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Zhou Y; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Li T; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Buchanan FG; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Ferguson DC; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Kurnick MD; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Kapecki N; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Lai A; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Michaelides MR; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Penning TD; Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Oct 10; Vol. 67 (19), pp. 17033-17052. Date of Electronic Publication: 2024 Sep 30.
DOI:	10.1021/acs.jmedchem.4c01451
Abstrakt:	Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of in vivo target engagement are needed to fully evaluate the potential use of MerTK inhibitors as cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.5 MerTK inhibitors bearing an azetidine-benzoxazole substituent. Compound 31 potently engages the target in vivo and demonstrates single agent activity in the immune-driven MC-38 murine syngeneic tumor model.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu