MODULATING THE MITOTIC KINASE FUNCTION OF AURORA-A WITH PROTEIN-PROTEIN INTERACTION INHIBITORS
| Componente | Categoria |
|---|---|
| Dalila Boi | Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca |
| Componente | Qualifica | Struttura | Categoria |
|---|---|---|---|
| Giulia Guarguaglini | Ricercatore | Istitute of Molecular Biology and Pathology - National Research Council | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca |
| Lee McDermott | Assistant Professor | University of Pittsburgh - Drug Discovery Institute | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca |
Background
Mitotic protein kinases are key regulators of cell division, and their overexpression drives oncogenesis, by causing genomic instability and aneuploidy. Accordingly, significant efforts have been recently concentrated on inhibitors targeting the ATP binding site of mitotic kinases for therapeutic purposes. Despite promising pre-clinical data, these compounds are displaying moderate effects in clinical trials; critical issues are mainly related to the lack of selectivity towards other kinases.
Hypothesis
Targeting mitotic kinases and their specific activators with protein-protein interaction (PPI) inhibitors could lead to anti-cancer drugs with increased selectivity. To test this hypothesis, the complex of the Aurora-A mitotic kinase and its activator TPX2 will be investigated, as it represents an intriguing paradigm. Indeed, the overexpression of Aurora-A and TPX2 is strongly correlated with a
wide spectrum of human cancers and a poor prognosis.
Aims
We have recently identified the first small-molecules disrupting the interaction between Aurora-A and TPX2, with confirmed activity both in vitro and in cultured cells. Based on these grounds, the main aims of the project are: 1) hit-to-lead optimization of novel PPI inhibitors of the Aurora-A/TPX2 complex; 2) investigation of the effects of the optimized hits in colon and breast cancer cells.
Expected Results
We expect to obtain: 1) compounds with improved potency and drug-likeness over early hits; 2) an in-depth understanding of the therapeutic value of targeting the Aurora-A/TPX2 complex using PPI inhibitors; 3) an optimized methodology platform, ready to be applied to other drug screening protocols involving mitotic kinases.
Application Potentialities
The identified PPI inhibitors will constitute lead compounds for further development towards pioneering anti-cancer drugs. Likewise, they will represent the proof-of-concept that a new strategy can be exploited to widen the pool of druggable kinases.