Pharmacophore guided diversity-oriented synthesis and its application in discovering inhibitors of protein-protein interactions between RAD51 and BRCA2

Project Information

Pharmcophore-DOS

Grant agreement ID: 654912

DOI

10.3030/654912

Project closed

EC signature date 25 March 2015

Start date 1 June 2015

End date 31 May 2017

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 195 454,80

EU contribution

€ 195 454,80

Coordinated by

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 1 - Pharmcophore-DOS (Pharmacophore guided diversity-oriented synthesis and its application in discovering inhibitors of protein-protein interactions between RAD51 and BRCA2)

Reporting period: 2015-06-01 to 2017-05-31

Summary of the context and overall objectives of the project

Given the difficulty in drug discovery, in particular when protein-protein interactions are targeted, we proposed a innovative strategy to identify hits and lead compounds for non- or difficult-drugged targets. Such an approach could accelerate the drug discovery and enhance the possibility of success in launching novel therapy to suffering patients. In our research, this novel strategy was developed and validated, and is hopeful to be expanded to more targets.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

• Following the novel strategy proposed, corresponding pharmocophore models were established via a structure-based approach.
• As unforeseeable difficulty was encountered in targeting RAD51 and BRAC2, we switched our target to the protein interface between the α and β subunits of CK2. As this proposal focused on the development and validation of this innovative strategy, the change of target showed no influence on objectives and expected outcomings.
• Pharmacophore models of both targets were established.
• Based on the pharmocophore model established (described in previous report), five compound libraries were designed, virtually evaluated and synthesized.
• The Synthesized are evaluated for their ability to bind to the target and potency in disturbing Protein-protein interaction via X-ray crystallography and FP assays, which are currently still ongoing.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The ability of discovering new drugs are expected to be further enhanced with the innovative strategy, i.e. pharmacophore guided diversity-oriented synthesis. After validation, this novel approach could be employed by other researcher as well and thus push the development of now therapies for unmet medical needs. Such a progress is welcome by suffering patents and their families and could also save hundreds of billions of public health costs.

Pharmacophore model on the protein-protein interface of the α and β subunits of CK2