Structural basis for the design of allosteric inhibitors of the Aurora kinase A enzyme in the cancer chemotherapy

Author(s)

de Souza, Valeria Barbosa ^[1] ; Kawano, Daniel Fabio ^{[2, 3]}

Affiliation

^[1] Univ Campinas UNICAMP, Fac Med Sci, Dept Pharmacol, Campinas, SP - Brazil

^[2] Univ Campinas UNICAMP, Inst Chem, Campinas, SP - Brazil

^[3] Univ Campinas UNICAMP, Fac Pharmaceut Sci, Rua Candido Portinari 200, BR-13083871 Campinas, SP - Brazil

• Document type: Review article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1864, n. 1 JAN 2020.
• Web of Science Citations: 0

Abstract

Aurora kinases are essential enzymes for the control of cell cycle. The specific role of aurora kinase A (AURKA) is the regulation of spindle assembly and stability by promoting centrosome maturation and separation. Because AURKA is an essential protein for the normal occurrence of the cycle, mutations and deregulations in the activities of this protein are associated with several cancers. The kinase activity of AURKA is controlled by autocatalytic phosphorylation, which is facilitated after binding to a regulator protein, the Target Protein for Xenopuskinesin-like protein 2 (TPX2). Scope of review: This review highlights the physiological and pathophysiological properties of AURKA, the structure of the AURKA/TPX2 complex and the main structural features that can be explored for the design of selective AURKA inhibitors. Major conclusions: The design of selective AURKA inhibitors remains as a challenge as most of the currently available inhibitors target only the ATP binding cleft and are nonselective among kinases. However, by exploring the inactive form of the kinase, researchers get access to an adjacent hydrophobic pocket, allowing the design of more selective inhibitors. Additionally, the possibility of designing potent allosteric AURKA inhibitors look very promising from the clinical perspective, since it tends to yield the most selective class of compounds. General significance: Herein we detailed the binding modes of the most selective AURKA inhibitors currently reported. We believe this will aid researchers in defining the structural patterns necessary for selective AURKA inhibition, guiding the design of more potent compounds to be therapeutically explored in cancer patients. (AU)

• FAPESP's process: 18/08585-1 - Design and synthesis of new phospholipids that selectively induce the apoptosis of tumor cells via lipid rafts
• Grantee: Daniel Fábio Kawano
• Support Opportunities: Regular Research Grants