Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905)

Autor:	Matthew O. Duffey, Tricia J. Vos, Ruth Adams, Jennifer Alley, Justin Anthony, Cynthia Barrett, Indu Bharathan, Douglas Bowman, Nancy J. Bump, Ryan Chau, Courtney Cullis, Denise L. Driscoll, Amy Elder, Nancy Forsyth, Jonathan Frazer, Jianping Guo, Luyi Guo, Marc L. Hyer, David Janowick, Bheemashankar Kulkarni, Su-Jen Lai, Kerri Lasky, Gang Li, Jing Li, Debra Liao, Jeremy Little, Bo Peng, Mark G. Qian, Dominic J. Reynolds, Mansoureh Rezaei, Margaret Porter Scott, Todd B. Sells, Vaishali Shinde, Qiuju Judy Shi, Michael D. Sintchak, Francois Soucy, Kevin T. Sprott, Stephen G. Stroud, Michelle Nestor, Irache Visiers, Gabriel Weatherhead, Yingchun Ye, Natalie D’Amore
Rok vydání:	2011
Předmět:	Models Molecular Lactams Stereochemistry Cell Survival Protein Conformation Transplantation Heterologous Administration Oral Biological Availability Mice Nude Mitosis Antineoplastic Agents Cell Cycle Proteins Polo-like kinase Pharmacology Protein Serine-Threonine Kinases Crystallography X-Ray PLK1 Rats Sprague-Dawley Mice Structure-Activity Relationship Oral administration In vivo Cell Line Tumor Proto-Oncogene Proteins Drug Discovery Structure–activity relationship Animals Humans Chemistry Kinase Thiones Benzazepines Rats Transplantation Cell culture Molecular Medicine Drug Screening Assays Antitumor Neoplasm Transplantation
Zdroj:	Journal of medicinal chemistry. 55(1)
ISSN:	1520-4804
Popis:	This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::71360d15b44c1a6fcfa39401ef5e4fbf https://pubmed.ncbi.nlm.nih.gov/22070629 Zobrazit plný text záznamu