Emerging evidence indicates an important role of matrix metalloproteinases (MMP) in the early stage of cancer dissemination. Detailed structural information of MMPs has revealed that targeting the non-catalytic domain of proteases can overcome the lack of specificity and selectivity. Non-catalytic sites like, hemopexin (PEX) domain, which is indirectly crucial for the catalytic activity of MMPs and not highly conserved as compared to catalytic sites, can be an alternative site to target MMPs. Previously, Dufour et al utilized an in silico docking approach to screen a library of compounds against the MMP-9 PEX domain and identified several compounds with high docking scores. One of the compounds, N-(4-difluoromethoxyphenyl)-2-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-ylthio)acetamide (1403-A) exhibited micromolar affinity to MMP-9 with very good selectivity. This hit compound was also found to inhibit cell migration, proliferation, invasion, tumor growth and metastasis induced by MMP-9. In this work, 14 new analogs were designed based on computational modeling and synthesized. Biological evaluation of these new analogs showed that one of the compound Bcy exerts a substantially better effect on inhibiting proMMP-9 mediated migration than parental compound 1403-A as shown by a 2-D dot migration assay, which monitors proMMP-9 mediated cell migration. Bcy inhibits proMMP-9 mediated migration in a dose-dependent manner and may even have therapeutic effects in the nanomolar scale as shown by our EC50 curve. Bcy exerts a selective inhibition of proMMP-9 mediated migration over other homologous and non-homologous MMPs as evidenced by our 2-D dot migration assay. Further studies suggest that chronic exposure of cancer cells to Bcy has minimal cytotoxic effects in cells treated for multiple days. It was also found that Bcy inhibits cellular migration and has no observed off-target effects on the catalytic activity of MMPs as observed by our FITClabeled gelatin substrate degradation assay. The design, synthesis and biological evaluations of Bcy and its analogs will be presented.

Synthesis and biological evaluation of matrix metalloproteinase 9 inhibitors for cancer therapeutics

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.