학술논문
Mitigation of AcetylcholineEsterase Activity in the 1,7-Diazacarbazole Series of Inhibitors ofCheckpoint Kinase 1.
Document Type
Article
Author
Gazzard, Lewis; Williams, Karen; Chen, Huifen; Axford, Lorraine; Blackwood, Elizabeth; Burton, Brenda; Chapman, Kerry; Crackett, Peter; Drobnick, Joy; Ellwood, Charles; Epler, Jennifer; Flagella, Michael; Gancia, Emanuela; Gill, Matthew; Goodacre, Simon; Halladay, Jason; Hewitt, Joanne; Hunt, Hazel; Kintz, Samuel; Lyssikatos, Joseph
Source
Subject
*ACETYLCHOLINESTERASE
*CARBAZOLE derivatives
*DNA damage
*DNA repair
*CANCER treatment
*PHARMACODYNAMICS
*LABORATORY mice
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Language
ISSN
0022-2623
Abstract
Checkpointkinase 1 (ChK1) plays a key role in the DNA damage response, facilitatingcell-cycle arrest to provide sufficient time for lesion repair. Thisleads to the hypothesis that inhibition of ChK1 might enhance theeffectiveness of DNA-damaging therapies in the treatment of cancer.Lead compound 1(GNE-783), the prototype of the 1,7-diazacarbazoleclass of ChK1 inhibitors, was found to be a highly potent inhibitorof acetylcholine esterase (AChE) and unsuitable for development. Acampaign of analogue synthesis established SAR delineating ChK1 andAChE activities and allowing identification of new leads with improvedprofiles. In silico docking using a model of AChE permitted rationalizationof the observed SAR. Compounds 19(GNE-900) and 30(GNE-145) were identified as selective, orally bioavailableChK1 inhibitors offering excellent in vitro potency with significantlyreduced AChE activity. In combination with gemcitabine, these compoundsdemonstrate an in vivo pharmacodynamic effect and are efficaciousin a mouse p53 mutant xenograft model. [ABSTRACT FROM AUTHOR]