Fragment-based approaches to the design of candidate drugs that interrupt protein-protein interactions involved in cell regulation (360G-Wellcome-091058_Z_09_Z)

£1,087,754

The use of fragment-based drug discovery to identify novel drug candidates that modulate the BRCA2-RAD51 interaction for the treatment of cancerThe Trust has awarded over £2.4 million to Chris Abell, Tom Blundell, Marko Hyvonen, Grahame McKenzie and Ashok Venkitaraman at the University of Cambridge to use fragment-based approaches to design and make molecules that disrupt the interaction of two important proteins in human cells, the recombinase RAD51 and the product of the breast cancer-associated gene BRCA2.These proteins are involved in the repair of DNA breakage, and blocking their interaction should result in sensitization of cancer cells to DNA damage, e.g. by radiation, or directly induce cancer cell death during proliferation. Potent compounds will be developed by synergistic use of X-ray crystallography and synthetic organic chemistry, and improved in a highly focused way to make sure they are safe and suitable for development into possible drug candidates. The lead compounds will be tested against different cancer cell lines to identify susceptible cancers, the most probable therapeutic target being lung cancer. This funding follows on directly from a Translation Award to pioneer the use of fragment-based approaches against protein-protein interactions. That project established the use of biophysical methods, especially NMR spectroscopy and X-ray crystallography to identify fragments that bound at specific sites on a protein interface and to iteratively grow these fragments into successively more potent compounds.

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Grant Details

Amount Awarded 1087754
Applicant Surname Abell
Approval Committee Seeding Drug Discovery Committee
Award Date 2009-11-06T00:00:00+00:00
Financial Year 2009/10
Grant Programme: Title Seeding Drug Discovery Award
Internal ID 091058/Z/09/Z
Lead Applicant Prof Christopher Abell
Other Applicant(s) Dr Grahame McKenzie, Prof Ashok Venkitaraman, Prof Marko Hyvönen, Prof Sir Tom Blundell
Partnership Value 1087754
Planned Dates: End Date 2013-12-31T00:00:00+00:00
Planned Dates: Start Date 2010-05-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England