期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 70, 期 -, 页码 758-767出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.10.052
关键词
ERK5 inhibitor; Kinase selectivity; Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one
资金
- NIH [P41 GM079575-03, CA079871, CA114059]
- Medical Research Council
- Michael J Fox foundation for Parkinson's disease research
- DSTT (AstraZeneca)
- DSTT (Boehringer-Ingelheim)
- DSTT (GlaxoSmithKline)
- DSTT (Merck KgaA)
- DSTT (Pfizer)
- Tobacco-Related Disease, Research Program of the University of California [19XT-0084]
- Spanish Ministerio de Educacion [BFU2007-60268]
- SGC, a registered charity [1097737]
- Canadian Institutes for Health Research
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Pfizer
- Eli Lilly
- Takeda
- AbbVie
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Wellcome Trust
- Medical Research Council [MC_UU_12016/2, MC_G1000735, MC_U127070193] Funding Source: researchfish
- MRC [MC_G1000735, MC_U127070193, MC_UU_12016/2] Funding Source: UKRI
The benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one core was discovered as a novel ERK5 (also known as MAPK7 and BMK1) inhibitor scaffold, previously. Further structure-activity relationship studies of this scaffold led to the discovery of ERK5-IN-1 (26) as the most selective and potent ERK5 inhibitor reported to date. 26 potently inhibits ERK5 biochemically with an IC50 of 0.162 +/- 0.006 mu M and in cells with a cellular EC50 for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 +/- 0.03 W. Furthermore, 26 displays excellent selectivity over other kinases with a KINOMEscan selectivity score (S-10) of 0.007, and exhibits exceptional bioavailability (F%) of 90% in mice. 26 will serve as a valuable tool compound to investigate the ERK5 signaling pathway and as a starting point for developing an ERK5 directed therapeutic agent. (C) 2013 Elsevier Masson SAS. All rights reserved.
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