Novel phenanthridin-6(5H)-one derivatives as potent and selective BET bromodomain inhibitors: Rational design, synthesis and biological evaluation

Autor:	Zhengrong Shen, Wenhai Huang, Wang Zunyuan, Shenxin Zeng, Shu Wang, Liang Meihao, Zhimin Zhang, Ma Zhen, Zhang Chixiao, Yanle Zhi
Rok vydání:	2019
Předmět:	Models Molecular Administration Oral Drug design Antineoplastic Agents Apoptosis Cell Cycle Proteins chemical and pharmacologic phenomena Pharmacology Crystallography X-Ray 01 natural sciences Rats Sprague-Dawley BET inhibitor Structure-Activity Relationship 03 medical and health sciences Drug Discovery Animals Humans Cell Proliferation 030304 developmental biology Biological evaluation 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Rational design Nuclear Proteins hemic and immune systems General Medicine Phenanthridines Rats 0104 chemical sciences Bromodomain Drug Design Microsomes Liver Female Antiproliferative effect Cancer cell lines Transcription Factors
Zdroj:	European Journal of Medicinal Chemistry. 179:502-514
ISSN:	0223-5234
Popis:	Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 μM) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4841c6efc51c5e325eb9e94a626d82bc https://doi.org/10.1016/j.ejmech.2019.06.067 Zobrazit plný text záznamu Full Text from ScienceDirect