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Allosteric Modulation of AURKA Kinase Activity via Disruption of its Protein-Protein Interaction with TPX2

last modified Jul 06, 2016 12:09 PM

The Venkitaraman group (in collaboration with researchers from the Department of Chemistry and Department of Biochemistry) have recently reported (in Scientific Reports) on the discovery of AurkinA, a novel inhibitor of AURKA (Aurora kinase A)-TPX2 interaction (Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2).

AURKA belongs to a family of Ser/Thr kinases, which are responsible for progression through mitotic cell division. It has been particularly implicated in many events surrounding transit through the G2 to M phases of the cell cycle and during mitotic cell division. Interaction with its protein partner, TPX2, promotes localisation to mircrotubules in the mitotic spindle and also modulates the catalytic activity of AURKA. Overexpression of AURKA is a common occurence in many cancer types, with efforts being made to therapeutically target its activity (using ATP-competitive inhibitors) in clinical trials. More recently, interest has shifted to allosteric inhibition of AURKA using compounds that interfere with interaction with TPX2.

This study demonstrated that AurkinA (the drug-like inhibitor of AURKA) disrupts the AURKA-TPX2 interaction and mislocalises the kinase from the mitotic spindle in cells. Unexpectedly, AurkinA binding to the Y-pocket (the pocket occupied by TPX2 in the AURKA-TPX2 complex) led to conformational alterations in AURKA that were distinct from those induced by TPX2 binding. These findings are thought to have implications for the chemical biology and selective therapeutic targeting of structurally related kinases.

Publication Details:

Janeček M, Rossmann M, Sharma P, Emery E, Huggins DJ, Stockwell S, Stokes JE, Tan YS, Almeida EG, Hardwick B, Narvaez AJ, Hyvönen M, Spring D, Grahame McKenzie G, Venkitaraman AR. Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2. Scientific Reports. 2016 Jun 24;6:28528. doi: 10.1038/srep28528.

Further information on research carried out by the Venkitaraman group can be found here.