4QYH

CHK1 kinase domain in complex with diazacarbazole GNE-783

Summary for 4QYH

• Entry DOI: 10.2210/pdb4qyh/pdb
• Related: 4QYE 4QYF 4QYG
• Descriptor: Serine/threonine-protein kinase Chk1, 3-[4-(4-methylpiperazin-1-yl)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: 2
• Total formula weight: 69147.27

Authors

Wiesmann, C.,Wu, P. (deposition date: 2014-07-24, release date: 2014-12-17, Last modification date: 2024-02-28)

Primary citation

Gazzard, L.,Appleton, B.,Chapman, K.,Chen, H.,Clark, K.,Drobnick, J.,Goodacre, S.,Halladay, J.,Lyssikatos, J.,Schmidt, S.,Sideris, S.,Wiesmann, C.,Williams, K.,Wu, P.,Yen, I.,Malek, S.
Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1.
Bioorg.Med.Chem.Lett., 24:5704-5709, 2014

PubMed Abstract: Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1.

PubMed: 25453805
DOI: 10.1016/j.bmcl.2014.10.063

Experimental method

X-RAY DIFFRACTION (1.9 Å)