PDBsum entry 2ywp

Transferase

PDB id: 2ywp

Contents

Protein chain

269 a.a. *

Ligands

A42

* Residue conservation analysis

PDB id:

2ywp

Name:

Transferase

Title:

Crystal structure of chk1 with a urea inhibitor

Structure:

Serine/threonine-protein kinase chk1. Chain: a. Fragment: residues 2-270. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: chek1, chk1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.90Å R-factor: 0.241 R-free: 0.297

Authors:

C.Park

Key ref:

G.Li et al. (2006). 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. PubMed id: 16446090 DOI: 10.1016/j.bmcl.2006.01.028

Date:

21-Apr-07 Release date: 08-May-07

Supersedes:

2fga

Protein chain

O14757  (CHK1_HUMAN) -  Serine/threonine-protein kinase Chk1 from Homo sapiens

Seq: 476 a.a.

Struc: 269 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmcl.2006.01.028

Bioorg Med Chem Lett 16:2293-2298 (2006)

PubMed id: 16446090

Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors.

G.Li, L.A.Hasvold, Z.F.Tao, G.T.Wang, S.L.Gwaltney, J.Patel, P.Kovar, R.B.Credo, Z.Chen, H.Zhang, C.Park, H.L.Sham, T.Sowin, S.H.Rosenberg, N.H.Lin.

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.