G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer.
Rigorous quality control steps, termed checkpoints, tightly regulate progression through the cell cycle. DNA-damaging chemotherapy and radiation activate functional cellular checkpoints. These checkpoints can facilitate DNA repair and promote cell death in unrepaired cells. There are at least three DNA damage checkpoints - at G1/S, S, and G2/M - as well as a mitotic spindle checkpoint. Most cancer cells harbour mutations in tumour suppressors and/or oncogenes, which impair certain cell checkpoints. Inhibiting the remaining cell checkpoints - particularly after exposure of cancer cells to chemotherapy and/or radiation - allows cell death, a strategy now being employed in cancer therapeutics. With our increasing knowledge of cell cycle regulation, many compounds have been developed to inhibit specific checkpoint components, particularly at the G2/M transition. One such target is checkpoint kinase-1 (Chk1). We review here the molecular framework of the cell cycle, the rationale for targeting Chk1, the preclinical concepts related to the development of Chk1 inhibitors, and the efficacy and safety results from Chk1 inhibitors now in phase I/II trials.
Bucher
N
N
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Britten
C D
CD
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002453:Cell Cycle; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D016195:G2 Phase; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1