Exosite based inhibition of the MMP-13 hemopexin domain as a potential wide range therapeutic strategy for breast and colorectal cancers

This project aims to develop promising therapeutic strategies against breast and colorectal cancers. Matrix metalloproteinase-13 (MMP-13) has long been identified as a target of inhibition in the treatment of osteoarthritis (OA), rheumatoid arthritis (RA) and breast cancer. Recent reports suggest that selective inhibition of MMP-13 can be achieved by targeting the hemopexin (Hpx) domain of the protease which is critical for its substrate specificity. For the first time, in our earlier cheminformatics study, we targeted putative characteristic hemopexin residues (HCR- 13pf) of MMP-13 and identified seven lead molecules using high throughput virtual screening. As preliminary data, we present here the experimental validation of these lead compounds. Two compounds exhibit potential inhibitory activity against MMP-13. Our results support that these compounds can serve as building blocks for designing therapeutic possibilities for the treatment of breast and colorectal cancers. In this proposal our specific aims are: 1. Synthesis of a small library of compounds 5 and 6: 2. Determine inhibition of MMP13 activity of new derivatives of compounds 5 and 6 3. Confirm anti-tumor effects of compounds 5 and 6 and their new derivatives: 4. Determine heparin-enhanced detection of MMP13 activity using gelatin zymography: 5. Determine anti-invasive effects of compounds 5 and 6 and their derivatives 6. Investigate in vivo efficacies of compounds 5 and 6 and their derivatives. 7. Crystal structure of the Hpx domain of MMP-13 in complex with compounds 5 and 6 and their derivatives.