Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones

Authors
Deng, XianmingElkins, Jonathan M.Zhang, JinweiYang, QingkaiErazo, TatianaGomez, NestorChoi, Hwan GeunWang, JinhuaDzamko, NicolasLee, Jiing-DwanSim, TaeboKim, NamDooAlessi, Dario R.Lizcano, Jose M.Knapp, StefanGray, Nathanael S.
Issue Date
2013-12
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.70, pp.758 - 767
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 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.
Keywords
ACTIVATED PROTEIN-KINASE; PROSTATE-CANCER; IN-VIVO; INHIBITOR SELECTIVITY; PARKINSON DISEASE; EXPRESSION; CELLS; LRRK2; POLO-LIKE-KINASE-1; CARCINOMA; ACTIVATED PROTEIN-KINASE; PROSTATE-CANCER; IN-VIVO; INHIBITOR SELECTIVITY; PARKINSON DISEASE; EXPRESSION; CELLS; LRRK2; POLO-LIKE-KINASE-1; CARCINOMA; ERK5 inhibitor; Kinase selectivity; Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one
ISSN
0223-5234
URI
https://pubs.kist.re.kr/handle/201004/127405
DOI
10.1016/j.ejmech.2013.10.052
Appears in Collections:
KIST Article > 2013
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