Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer.
Over the past decade, protein kinases have emerged as a group of molecular targets with the potential to be "cancer-specific", allowing the selective targeting of cancer cells versus normal cells. These selective anticancer drugs would eliminate the cytotoxic side effects that are associated with conventional cancer chemotherapy. This article will focus on two emerging and less-explored protein serine/threonine kinase targets: PKB/Akt and checkpoint kinase 1 (Chk1). Protein kinase B/Akts are a group of serine/threonine kinases that are overexpressed in a variety of human tumors. An Akt inhibitor would target the imbalance of pro-versus anti-apoptosis regulation in cancerous as compared to healthy cells. Thus, a greater therapeutic window than conventional cytotoxic chemotherapy is expected. Cell-cycle checkpoints have become attractive targets since some of them, such as the G1/S checkpoint, are defective in most tumor cells. Inhibition of one or more of the remaining checkpoint(s) could make cancerous cells more sensitive than healthy cells toward DNA damaging agents or radiation therapy. Among the checkpoint kinases, Chk1 appears to be an attractive molecular target. Chk1 blocks the activation of the Cdc2-cyclin B kinase complex, and hence entry into mitosis, by disrupting the translocation of the phosphatase Cdc25C from the cyotoplasm to the nucleus. A limited number of small molecule inhibitors in this emerging field and their mode of action will be reviewed.
Li
Qun
Q
Abbott Laboratories, Cancer Research, Global Pharmaceutical Discovery, R47S, AP10, 100 Abbott Park Rd, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com
Zhu
Gui-Dong
GD
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D017386:Sequence Homology, Amino Acid
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; C494918:AKT1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt