Aurora kinases and their inhibitors: more than one target and one drug.
Dependent on the degree of inhibition of different Aurora kinase family members, various events in mitosis are affected, resulting in differential cellular responses. These different cellular responses have to be considered in the clinical development of the small molecule inhibitors with respect to the chosen indications, schedules and appropriate endpoints. Here the properties of the most advanced small molecule Aurora kinase inhibitors are compared and a case report on the development of PHA-739358 - a spectrum selective kinases inhibitor with a dominant phenotype of Aurora kinases inhibition, which is currently being tested in clinical trials - is discussed. One of the selection criteria for this compound was its property of inhibiting more than one cancer relevant target, such as Abl wild-type and the multidrug resistant Abl T315I mutant. This opens another path for clinical development in CML, and clinical trials are underway to evaluate the activity in patients suffering from chronic myelogenous leukemia, who developed resistance to currently approved treatments.
Carpinelli
Patrizia
P
Nerviano Medical Sciences Srl. Viale Pasteur 10, 20014 Nerviano (Mi), Italy.
Moll
Jürgen
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064127:Aurora Kinases; D014408:Biomarkers, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008495:Medical Oncology / Q000379:methods; D051379:Mice; D008938:Mitosis; D008956:Models, Chemical; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases