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.
In our view, our expertise in PPI design and the results already achieved (18), constitute the main strengths of the proposal, and will permit the integrated application of forefront methodologies in the field of kinase drug discovery.
At the same time, our willingness to pursue both the basic and the applied aspects of the project in a highly focused workflow will allow efficient translation of proof of concepts into clinically useful agents for innovative anti-cancer therapies.
The following advances in the field of kinase drug discovery are therefore envisaged:
- experimental validation of the whole Aurora-A/TPX2 oncogenic unit as a novel therapeutic target with improved druggability and specificity profiles over its single components;
- development of allosteric PPI kinase inhibitors: such molecules would be highly innovative compared to type I inhibitors currently in clinical trials, and would represent a new paradigm to target the kinome.
A key point in the Horizon2020 program ("Curing, treating disease: transferring fundamental knowledge to clinical practice") is aimed at improving the quality and duration of life for the European citizens. Fighting cancer is one of the top research priorities within the European Union.
In this regard, results obtained in this project may be of relevance for several aspects:
- novelty: targeting protein-protein interactions is a relatively novel approach and thus far a few successful examples have been described; the identification, during the development of the project, of lead compounds able to inhibit the Aurora-A/TPX2 interaction would therefore constitute, in the first place, a paradigmatic example useful for the whole field of drug design of PPI inhibitors of mitotic kinases;
- proof of concept: if we describe a strong anti-proliferative effect following treatment of cell cultures with such molecules, this would indicate that inhibiting the binding of TPX2 to Aurora-A may constitute a novel valuable therapeutic anti-cancer approach, providing a specific and highly innovative method to inactivate the kinase. This result would significantly contribute to the field of mitotic kinase targeting as anti-cancer strategy, and pave the way to turn promising hit molecules into anti-cancer therapies. The molecules that we propose to develop would therefore have a strong potential to be transferred to the clinical phase, thanks also to the interest demonstrated by a leading Italian pharmaceutical company, the Menarini group;
- research tools: the identified compounds will constitute in any case excellent investigation tools as chemical reagents in the field of basic research, finalised to the study of mitotic regulation. In this framework, investigating the cellular response to such compounds will provide further knowledge towards the understanding of how the Aurora-A/TPX2 complex acts during cell division;
- personalized cancer therapy: the overexpression of both components of the Aurora-A/TPX2 complex has been associated with particularly aggressive tumor stages, such as with the transition from adenoma to carcinoma in colorectal tumors and with breast cancer. In the personalized medicine field, the results of this project may provide the basis to stratify patients before chemotherapeutic treatment, based on the use of Aurora-A and TPX2 as specific biomarkers, with the goal of optimizing clinical outcomes.