Small Molecule Anti-Cancer Compounds Selectively Target the Hemopexin Domain of Matrix Metalloproteinase-9 (MMP-9)

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Acknowledgements: We thank the members of the Sampson, Zucker and Cao labs for their insightful discussions and suggestions on the manuscript, and Kevin Zarrabi for his help with editing and Dr. Francis Johnson for his critical reading. We are also grateful to J. Shipman and T. Balius for their input on the molecular DOCKing studies. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Lack of target specificity by existing matrix metalloproteinase (MMP) inhibitors has hindered anti-metastatic cancer drug discovery. Inhibitors that bind to non-catalytic sites of MMPs and disrupt protease signaling function have the potential to be more specific and selective. In this work, compounds that target the hemopexin (PEX) domain of MMP-9 were identified using an in silico docking approach and evaluated using biochemical and biological approaches. Two of the selected compounds interfere with MMP-9-mediated cancer cell migration and proliferation in cells expressing exogenous or endogenous MMP-9. Furthermore, these inhibitors do not modulate MMP-9 catalytic activity. The lead compound,