4RVM

CHK1 kinase domain with diazacarbazole compound 19

Summary for 4RVM

• Entry DOI: 10.2210/pdb4rvm/pdb
• Descriptor: Serine/threonine-protein kinase Chk1, 3-[4-(piperidin-1-ylmethyl)phenyl]-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile (3 entities in total)
• Functional Keywords: protein kinase, phosphotransfer catalyst, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 34572.65

Authors

Gazzard, L.,Blackwood, E.,Burton, B.,Chapman, K.,Chen, H.,Crackett, P.,Drobnick, J.,Ellwood, C.,Epler, J.,Flagella, M.,Goodacre, S.,Halladay, J.,Hunt, H.,Kintz, S.,Lyssikatos, J.,MacLeod, C.,Ramiscal, S.,Schmidt, S.,Seward, E.,Wiesmann, C.,Williams, K.,Wu, P.,Yee, S.,Yen, I.,Malek, S. (deposition date: 2014-11-26, release date: 2015-06-03, Last modification date: 2023-09-20)

Primary citation

Gazzard, L.,Williams, K.,Chen, H.,Axford, L.,Blackwood, E.,Burton, B.,Chapman, K.,Crackett, P.,Drobnick, J.,Ellwood, C.,Epler, J.,Flagella, M.,Gancia, E.,Gill, M.,Goodacre, S.,Halladay, J.,Hewitt, J.,Hunt, H.,Kintz, S.,Lyssikatos, J.,Macleod, C.,Major, S.,Medard, G.,Narukulla, R.,Ramiscal, J.,Schmidt, S.,Seward, E.,Wiesmann, C.,Wu, P.,Yee, S.,Yen, I.,Malek, S.
Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.
J.Med.Chem., 58:5053-5074, 2015

PubMed Abstract: Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

PubMed: 25988399
DOI: 10.1021/acs.jmedchem.5b00464

Experimental method

X-RAY DIFFRACTION (1.86 Å)