2YWP

Crystal Structure of CHK1 with a Urea Inhibitor

Replaces:  2FGA

Summary for 2YWP

• Entry DOI: 10.2210/pdb2ywp/pdb
• Related: 2AYP
• Descriptor: Serine/threonine-protein kinase Chk1, 1-(5-CHLORO-2,4-DIMETHOXYPHENYL)-3-(5-CYANOPYRAZIN-2-YL)UREA (2 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: 31402.47

Authors

Park, C. (deposition date: 2007-04-21, release date: 2007-05-08, Last modification date: 2024-03-13)

Primary citation

Li, G.,Hasvold, L.A.,Tao, Z.-F.,Wang, G.T.,Gwaltney II, S.L.,Patel, J.,Kovar, P.,Credo, R.B.,Chen, Z.,Zhang, H.,Park, C.,Sham, H.L.,Sowin, T.,Rosenberg, S.H.,Lin, N.-H.
Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors
Bioorg.Med.Chem.Lett., 16:2293-2298, 2006

PubMed Abstract: Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N'-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50=1.7 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity.

PubMed: 16446090
DOI: 10.1016/j.bmcl.2006.01.028

Experimental method

X-RAY DIFFRACTION (2.9 Å)