Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors

Autor:	Kouhei Honda, Betty Lam, Xiaodong Cao, Tomohiro Kawamoto, David J. Hosfield, Takashi Ichikawa, Hua Zou, Srinivasa Reddy Natala, Kiryanov Andre A, Jones Benjamin, Yuichi Hikichi, Robert J. Skene, Jeffrey A. Stafford, Feher Victoria, Christopher McBride, Noriko Uchiyama, Yan Liu, Lilly Zhang
Rok vydání:	2016
Předmět:	0301 basic medicine Stereochemistry Clinical Biochemistry Pharmaceutical Science Cell Cycle Proteins Polo-like kinase Protein Serine-Threonine Kinases Biochemistry PLK1 03 medical and health sciences Histone H3 Mice Structure-Activity Relationship 0302 clinical medicine In vivo Proto-Oncogene Proteins Drug Discovery medicine Animals Humans Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Molecular Structure Chemistry Pteridines Organic Chemistry Imidazoles Bioavailability Enzyme Activation 030104 developmental biology Enzyme 030220 oncology & carcinogenesis Drug Design Molecular Medicine Phosphorylation Heterografts Female HT29 Cells Pteridine medicine.drug
Zdroj:	Bioorganicmedicinal chemistry letters. 27(5)
ISSN:	1464-3405
Popis:	Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8509d8ca6026c869b9f2b4ac622c74c4 https://pubmed.ncbi.nlm.nih.gov/28169164 Zobrazit plný text záznamu Full Text from ScienceDirect