2E9N

Structure of h-CHK1 complexed with A767085

Summary for 2E9N

• Entry DOI: 10.2210/pdb2e9n/pdb
• Related: 2AYP 2E9O 2E9P 2E9U 2E9V 2FGA 2GHG
• Descriptor: Serine/threonine-protein kinase Chk1, 3-(4'-HYDROXYBIPHENYL-4-YL)-N-(4-HYDROXYCYCLOHEXYL)-1,4-DIHYDROINDENO[1,2-C]PYRAZOLE-6-CARBOXAMIDE (3 entities in total)
• Functional Keywords: protein-inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 31534.28

Authors

Park, C. (deposition date: 2007-01-26, release date: 2008-01-29, Last modification date: 2024-03-13)

Primary citation

Tong, Y.,Claiborne, A.,Stewart, K.D.,Park, C.,Kovar, P.,Chen, Z.,Credo, R.B.,Gu, W.Z.,Gwaltney, S.L.,Judge, R.A.,Zhang, H.,Rosenberg, S.H.,Sham, H.L.,Sowin, T.J.,Lin, N.H.
Discovery of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of potent and selective checkpoint kinase 1 inhibitors.
Bioorg.Med.Chem., 15:2759-2767, 2007

PubMed Abstract: A new class of checkpoint kinase 1 (CHK-1) inhibitors bearing a 1,4-dihydroindeno[1,2-c]pyrazole core was developed after initial hits from high throughput screening. The efficient hit-to-lead process was facilitated by X-ray crystallography and led to potent inhibitors (<10nM) against CHK-1. X-ray co-crystal structures of bound inhibitors demonstrated that two sub-series of this class of compounds, exemplified by 21 and 41, exhibit distinctive hydrogen bonding patterns in the specificity pocket of the active site. Two compounds, 41 and 43, were capable of potentiating doxorubicin and camptothecin, both DNA-damaging agents, in cell proliferation assays (MTS and soft agar assays) and abrogating G2/M checkpoint in a mechanism-based FACS assay.

PubMed: 17287122
DOI: 10.1016/j.bmc.2007.01.012

Experimental method

X-RAY DIFFRACTION (2.5 Å)