Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors

Autor:	Kenneth D. Rice, Yong Wang, Lynne Canne Bannen, Morrison B. Mac, Vasu Jammalamadaka, Simona Costanzo, Maurizio Franzini, Erick Wang Co, Nicole Miller, Larisa Dubenko, Steven Charles Defina, Joerg Bussenius, Neel Kumar Anand, Douglas Laird, David J. Matthews, John M. Nuss, Jason Jevious Parks, Amy Lew Tsuhako, Rhett Ronald Klein, Donna T. Le, Tsze H. Tsang, Baili Chen, Charles M. Blazey, Moon Hwan Kim, David W. Markby, Richard George Khoury, Wei Xu, Diva Sze-Ming Chan, Owen Joseph Bowles, Stefan Engst, Ping Huang
Rok vydání:	2011
Předmět:	Male High-throughput screening Clinical Biochemistry Pharmaceutical Science Administration Oral Biological Availability Antineoplastic Agents Pharmacology Biochemistry Pyrazolopyrimidine chemistry.chemical_compound Inhibitory Concentration 50 Mice Structure-Activity Relationship Pharmacokinetics Cell Line Tumor Drug Discovery Animals Humans Molecular Biology Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Chemistry Kinase Organic Chemistry Ribosomal Protein S6 Kinases 70-kDa Xenograft Model Antitumor Assays High-Throughput Screening Assays Rats Pyrimidines Solubility Ribosomal protein s6 Drug Design Molecular Medicine Pyrazoles Lead compound Signal Transduction
Zdroj:	Bioorganicmedicinal chemistry letters. 22(6)
ISSN:	1464-3405
Popis:	The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure–activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::82e39bdc172bd771c8f3fbd8b679a60b https://pubmed.ncbi.nlm.nih.gov/22342124 Zobrazit plný text záznamu Full Text from ScienceDirect