SYNTHESIS AND EVALUATION OF NOVEL MEMBRANE TYPE 1 MATRIX METALLOPROTEINASE (MT1-MMP) INHIBITORS

Membrane type 1 matrix metalloproteinase (MT1-MMP)/(MMP-14) is a type I transmembrane metalloproteinase involved in degradation of extracellular matrix (ECM) and non-ECM substrates. MT1-MMP facilitates cell migration, and is associated with multiple physiological processes, such as morphogenesis, skeletal development, and wound healing. However, MT1-MMP overexpression causes cancer cell invasion, metastasis, and growth. Therefore, MT1-MMP activities should be regulated either through endogenous tissue inhibitors of MMPs (TIMPs) or novel synthetic MT1-MMP inhibitors. The specific aim of this thesis work is the synthesis and evaluation of novel MT1-MMP C6 and C12 hit inhibitors obtained from one-bead one-compound (OBOC) libraries in order to aid in the discovery and development of effective treatments for many cancers, including melanoma, small cell lung cancer, head and neck carcinoma, bladder cancer, breast cancer, etc.