PDBsum entry 2w7x

Transferase

PDB id: 2w7x

Contents

Protein chain

285 a.a. *

Ligands

D1A

NO3

EDO ×2

Metals

_MG

Waters ×193

* Residue conservation analysis

PDB id:

2w7x

Name:

Transferase

Title:

Cellular inhibition of checkpoint kinase 2 and potentiation of cytotoxic drugs by novel chk2 inhibitor pv1019

Structure:

Serine/threonine-protein kinase chk2. Chain: a. Fragment: catalytic domain, residues 210-531. Synonym: checkpoint kinase 2, cds1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.07Å R-factor: 0.195 R-free: 0.220

Authors:

A.G.Jobson,G.T.Lountos,P.L.Lorenzi,J.Llamas,J.Connelly,J.E.Tropea, A.Onda,S.Kondapaka,G.Zhang,N.J.Caplen,J.H.Caredellina,A.Monks, C.Self,D.S.Waugh,R.H.Shoemaker,Y.Pommier

Key ref:

A.G.Jobson et al. (2009). Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]. J Pharmacol Exp Ther, 331, 816-826. PubMed id: 19741151

Date:

06-Jan-09 Release date: 22-Sep-09

Protein chain

O96017  (CHK2_HUMAN) -  Serine/threonine-protein kinase Chk2 from Homo sapiens

Seq: 543 a.a.

Struc: 285 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

J Pharmacol Exp Ther 331:816-826 (2009)

PubMed id: 19741151

Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide].

A.G.Jobson, G.T.Lountos, P.L.Lorenzi, J.Llamas, J.Connelly, D.Cerna, J.E.Tropea, A.Onda, G.Zoppoli, S.Kondapaka, G.Zhang, N.J.Caplen, J.H.Cardellina, S.S.Yoo, A.Monks, C.Self, D.S.Waugh, R.H.Shoemaker, Y.Pommier.

ABSTRACT

Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential.