@article{f334bc300eb44c868071982ac7cc66fc,
title = "Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones",
abstract = "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 IC 50 of 0.162 ± 0.006 μM and in cells with a cellular EC 50 for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 ± 0.03 μM. Furthermore, 26 displays excellent selectivity over other kinases with a KINOMEscan selectivity score (S10) 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.",
keywords = "Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)- one, ERK5 inhibitor, Kinase selectivity",
author = "Xianming Deng and Elkins, {Jonathan M.} and Jinwei Zhang and Qingkai Yang and Tatiana Erazo and Nestor Gomez and Choi, {Hwan Geun} and Jinhua Wang and Nicolas Dzamko and Lee, {Jiing Dwan} and Taebo Sim and Namdoo Kim and Alessi, {Dario R.} and Lizcano, {Jose M.} and Stefan Knapp and Gray, {Nathanael S.}",
note = "Funding Information: We wish to thank Life Technologies Corporation, SelectScreen Kinase Profiling Service for performing enzymatic biochemical kinase profiling, DiscovRx for performing KINOMEscan profiling. This work was supported by NIH grant P41 GM079575 -03 (N. Gray) and the Medical Research Council (D. Alessi), the Michael J Fox foundation for Parkinson's disease research (N. Gray & D. Alessi), the pharmaceutical companies supporting the DSTT ( AstraZeneca, Boehringer-Ingelheim , GlaxoSmithKline , Merck KgaA and Pfizer ) (D. Alessi), the NIH grant CA079871 and CA114059 (J.-D. Lee) and funds from the Tobacco-Related Disease, Research Program of the University of California , 19XT-0084, (J.-D. Lee), and by the Spanish Ministerio de Educaci{\'o}n grant BFU2007-60268 (J.M. Lizcano). JME, and SK are grateful for financial support by the SGC, a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research , the Canada Foundation for Innovation , Genome Canada , GlaxoSmithKline, Pfizer, Eli Lilly , Takeda , AbbVie , the Novartis Research Foundation , the Ontario Ministry of Research and Innovation and the Wellcome Trust . ",
year = "2013",
doi = "10.1016/j.ejmech.2013.10.052",
language = "English",
volume = "70",
pages = "758--767",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
}