TY - JOUR
T1 - Death by releasing the breaks
T2 - CHK1 inhibitors as cancer therapeutics
AU - Ma, Cynthia X.
AU - Janetka, James W.
AU - Piwnica-Worms, Helen
N1 - Funding Information:
A grant from the Komen Foundation to H.P.-W. and C.X.M. supports preclinical CHK1 inhibitor studies. H.P.-W. is an Investigator of the Howard Hughes Medical Institute.
PY - 2011/2
Y1 - 2011/2
N2 - Defects in p53 function, which occur frequently in human cancers due to mutations in TP53 or disruptions in the p53 regulatory pathway, render cells dependent on CHK1 (Checkpoint Kinase 1) to activate cell cycle checkpoints. In the presence of DNA damage or replication stress, inhibition of CHK1 leads to " mitotic catastrophe" and cell death in p53-deficient tumors while sparing p53-proficient cells. CHK1 inhibitors sensitize tumors to a variety of DNA-damaging agents or antimetabolites in preclinical models and are being evaluated in early phase clinical trials. In this review, we summarize recent advances and controversies in the development and application of CHK1 inhibitors as cancer therapeutics.
AB - Defects in p53 function, which occur frequently in human cancers due to mutations in TP53 or disruptions in the p53 regulatory pathway, render cells dependent on CHK1 (Checkpoint Kinase 1) to activate cell cycle checkpoints. In the presence of DNA damage or replication stress, inhibition of CHK1 leads to " mitotic catastrophe" and cell death in p53-deficient tumors while sparing p53-proficient cells. CHK1 inhibitors sensitize tumors to a variety of DNA-damaging agents or antimetabolites in preclinical models and are being evaluated in early phase clinical trials. In this review, we summarize recent advances and controversies in the development and application of CHK1 inhibitors as cancer therapeutics.
UR - http://www.scopus.com/inward/record.url?scp=79651470785&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79651470785&partnerID=8YFLogxK
U2 - 10.1016/j.molmed.2010.10.009
DO - 10.1016/j.molmed.2010.10.009
M3 - Review article
C2 - 21087899
AN - SCOPUS:79651470785
SN - 1471-4914
VL - 17
SP - 88
EP - 96
JO - Trends in Molecular Medicine
JF - Trends in Molecular Medicine
IS - 2
ER -