Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system.
The present review gives a perspective on the Aurora kinase family members, their function in normal cells, their role in cancer progression as well as their potential as target for anticancer treatment. Mitosis has been an important target for anticancer therapy development, leading to some specific drugs mainly addressing Tubulines, as a key structure of the mitotic spindle. Vinca alkaloids, taxanes or epotilones are good examples of conventionally developed antimitotic agents. However, novel classes of antineoplastic drugs are being studied, targeting the regulatory system that controls functional aspects of mitosis, such as Aurora or Polo-like kinases or Kinespondin inhibitors. The specific role of the different Aurora kinase proteins as regulator enzymes of the mitotic process in normal cells is discussed. Some of the mechanisms that link Aurora overexpression with cancer are also considered. Thereafter, the clinical and preclinical development of the different Aurora kinase inhibitors is presented. This is nowadays a very active area of therapeutic research and at least, sixteen new compounds are being studied as potential antineoplastic drugs. Most of them are in a very early phase of clinical development. However, we summarized the most recently published findings related with these drugs: main characteristics, way of administration, dose limiting toxicities and recommended doses for further studies. Another important aspect in Aurora kinase inhibition is the study and validation of potential biomarkers to optimize the clinical development. Several studies included pharmacodynamic assessments in normal blood cells, skin or/and tumor biopsies. Several proposals included a higher mitotic index, a decreased number of mitosis with bipolar spindles or normal alignment of chromosomes and inhibition of histone H3 phosphorylation. Future strategies and challenges for trials with Aurora kinase inhibitors are also discussed.
Pérez Fidalgo
José Alejandro
JA
Department of Hematology and Medical Oncology, INCLIVA, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.
Roda
Desamparados
D
Roselló
Susana
S
Rodríguez-Braun
Edith
E
Cervantes
Andrés
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use; D064127:Aurora Kinases; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D050258:Mitosis Modulators / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D000970:Antineoplastic Agents; D050258:Mitosis Modulators; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases