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The use of fragment-based drug discovery to develop novel small molecules that modulate the BRCA2-RAD51 interaction for the treatment of cancer

Objective

"The proposed research is to develop a small molecule as drug candidate compound for the treatment of cancer. We will use fragment-based methods to disrupt the protein-protein interaction between the human recombinase RAD51, and the hub protein BRCA2. This interaction is essential for DNA repair by homologous DNA recombination (HDR), a key cellular pathway involved in the resistance of cancer cells to ionizing radiation and radio-mimetic drugs. The target site (i.e. Velcro pocket) is unique to RAD51 and binds the LFDE tetrapeptide motifs in BRCA2. A suite of biophysical techniques will be used to identify small chemical fragments that specifically bind to the Velcro pocket. Fragment hits will be developed by structure-guided synthesis into more potent inhibitors that disrupt RAD51-BRAC2 interaction impairing the HDR process. We foresee that these small molecule inhibitors will have broad applicability in combination with existing cancer treatments. Moreover it can be anticipated that a small molecules that target only the Velcro site of RAD51, thereby preventing interaction with BRAC2 protein without precluding RAD51 oligomerization, will be valuable chemical tools to uncover different mechanistic aspects of the HDR process in cells."

Field of science

  • /natural sciences/biological sciences/genetics and heredity/dna
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/proteomics
  • /natural sciences/physical sciences/nuclear physics
  • /medical and health sciences/clinical medicine/cancer

Call for proposal

FP7-PEOPLE-2010-IIF
See other projects for this call

Funding Scheme

MC-IIF - International Incoming Fellowships (IIF)

Coordinator

THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Address
Trinity Lane The Old Schools
CB2 1TN Cambridge
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 201 049,60
Administrative Contact
Renata Schaeffer (Ms.)