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Title: Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor

Abstract

Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNA-damaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC{sub 50} = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATP-binding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2,more » located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1005491
Resource Type:
Journal Article
Journal Name:
Protein Sci.
Additional Journal Information:
Journal Volume: 18; Journal Issue: (1) ; 01, 2009
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; AFFINITY; APOPTOSIS; CELL CYCLE; CRYSTAL STRUCTURE; DESIGN; DNA DAMAGES; DNA REPAIR; DRUGS; ELECTRON DENSITY; INSTABILITY; NEOPLASMS; PHOSPHOTRANSFERASES; TARGETS; THERAPY

Citation Formats

Lountos, George T, Tropea, Joseph E, Zhang, Di, Jobson, Andrew G, Pommier, Yves, Shoemaker, Robert H, Waugh, David S, and NCI). Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor. United States: N. p., 2009. Web. doi:10.1002/pro.16.
Lountos, George T, Tropea, Joseph E, Zhang, Di, Jobson, Andrew G, Pommier, Yves, Shoemaker, Robert H, Waugh, David S, & NCI). Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor. United States. https://doi.org/10.1002/pro.16
Lountos, George T, Tropea, Joseph E, Zhang, Di, Jobson, Andrew G, Pommier, Yves, Shoemaker, Robert H, Waugh, David S, and NCI). 2009. "Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor". United States. https://doi.org/10.1002/pro.16.
@article{osti_1005491,
title = {Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor},
author = {Lountos, George T and Tropea, Joseph E and Zhang, Di and Jobson, Andrew G and Pommier, Yves and Shoemaker, Robert H and Waugh, David S and NCI)},
abstractNote = {Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNA-damaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC{sub 50} = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATP-binding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.},
doi = {10.1002/pro.16},
url = {https://www.osti.gov/biblio/1005491}, journal = {Protein Sci.},
number = (1) ; 01, 2009,
volume = 18,
place = {United States},
year = {Thu Mar 05 00:00:00 EST 2009},
month = {Thu Mar 05 00:00:00 EST 2009}
}