Aurora kinase inhibitors: Progress towards the clinic

Abstract

SummaryThe Aurora kinases (serine/threonine kinases) were discovered in 1995 during studies of mutant alleles associated with abnormal spindle pole formation in Drosophila melanogaster. They soon became the focus of much attention because of their importance in human biology and association with cancer. Aurora kinases are essential for cell division and are primarily active during mitosis. Following their identification as potential targets for cancer chemotherapy, many Aurora kinase inhibitors have been discovered, and are currently under development. The binding modes of Aurora kinase inhibitors to Aurora kinases share specific hydrogen bonds between the inhibitor core and the back bone of the kinase hinge region, while others parts of the molecules may point to different parts of the active site via noncovalent interactions. Currently there are about 30 Aurora kinase inhibitors in different stages of pre-clinical and clinical development. This review summarizes the characteristics and status of Aurora kinase inhibitors in preclinical, Phase I, and Phase II clinical studies, with particular emphasis on the mechanisms of action and resistance to these promising anticancer agents. We also discuss the validity of Aurora kinases as oncology targets, on/off-target toxicities, and other important aspects of overall clinical performance and future of Aurora kinase inhibitors.

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

“…As reviewed recently (24), an estimated 30 small-molecule inhibitors of Aurora kinases are currently undergoing preclinical and clinical evaluation (25)(26)(27)(28)(29)(30)(31). A number of these compounds are pan-Aurora kinase inhibitors that show inhibitory activity against both AAK and Aurora B kinase (ABK), as well as, in some cases, Aurora C kinase.…”

“…A number of these compounds are pan-Aurora kinase inhibitors that show inhibitory activity against both AAK and Aurora B kinase (ABK), as well as, in some cases, Aurora C kinase. However, evidence suggests that these pan-Aurora kinase inhibitors result in a phenotype reflective of ABK inhibition (1,24). In addition, a number of inhibitors selective for AAK or ABK are under development.…”

“…Such selective inhibition may result in a different therapeutic index and toxicity profile compared with pan-Aurora kinase inhibition, associated with the toxicities due to inhibition of either AAK or ABK, rather than both. The relative merits of selectively targeting AAK or ABK remain to be determined, although data suggest that both approaches offer antineoplastic activity (24,29). MLN8237 (alisertib) is an investigational, orally administered, small-molecule inhibitor that is selective for AAK (32,33).…”

Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

“…The therapeutic potential of Aurora-based targeted therapy is also being assessed in clinical trials (13), although none of them have specifically addressed TNBCs.…”

siRNA screening of the kinome identified Aurora A kinase as a therapeutic target gene in cervical cancer

“…To achieve this ultimate goal, different techniques have demonstrated the ability to identify novel target genes that when depleted affect only cancer cells but not normal cells (Kollareddy et al, 2012). In genetics, synthetic lethality is defined as a combination of mutations in two or more genes leading to cellular death (Dai et al, 2013, Dong et al, 2010, Porcelli et al, 2012.…”