Tubulin-associated drug targets: Aurora kinases, Polo-like kinases, and others.
Unrestrained cell division in cancer cells is dependent upon mitosis and its related processes. Therefore, a proven effective strategy in cancer treatment has been to interfere with the function of the mitotic spindle. Despite the success of these anti-mitotic agents, tubulin itself remains the only spindle-associated protein targeted by clinically approved agents. However, in recent years major advances have been achieved in targeting proteins that associate with tubulin and the mitotic spindle. Mitotic kinases such as the Aurora and Polo families are receiving significant attention due to their vital roles in assuring proper centrosome separation and chromosome segregation. Indeed, potent and selective inhibitors of these kinases have entered clinical trials. Similarly, the kinesins, particularly kinesin spindle protein (KSP), have emerged as potential therapeutic targets and inhibitors of KSP are currently under evaluation in the clinic. Although inhibitors have not been reported, mitotic checkpoint kinases (Mad2) and separase are additional potential targets for therapeutic intervention. Continued investigation of mechanisms regulating mitotic events will likely reveal additional proteins and pathways that could be potentially targeted and thereby provide more effective therapeutic options for cancer patients.
Warner
Steven L
SL
Translational Genomics Research Institute, Phoenix, AZ 85004, USA. swarner@tgen.org
Gray
Phillip J
PJ
Von Hoff
Daniel D
DD
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D000071877:Checkpoint Kinase 1; D010450:Endopeptidases; D042822:Genomic Instability; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors; D008938:Mitosis / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D064249:Securin; D064247:Separase; D014404:Tubulin / Q000187:drug effects; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D010450:Endopeptidases; D016547:Kinesins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D064249:Securin; D064247:Separase; D014404:Tubulin; D000097869:Polo-Like Kinase 1; C577987:ESPL1 protein, human