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, Xianming; Elkins, Jonathan M.; Zhang, Jinwei; Yang, Qingkai; Erazo, Tatiana; Gomez, Nestor; Choi, Hwan Geun; Wang, Jinhua; Dzamko, Nicolas; Lee, Jiing-Dwan; Sim, Taebo; Kim, NamDoo; Alessi, Dario R.; Lizcano, Jose M.; Knapp, Stefan; Gray, 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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