Defining and Engineering Specificity of Tissue Inhibitors of Metalloproteinases

Despite proven and important roles for matrix metalloproteinases (MMPs) in promoting cancer progression, small-molecule MMP inhibitors have fared poorly in clinical trials. This is in part because of a lack of selectivity, a problem that might be overcome by inhibitors highly selective for individual tumor-promoting MMPs.

An alternative to small-molecule matrix metalloproteinases inhibitor development could be the engineering of naturally occurring protein inhibitors of MMPs — tissue inhibitors of metalloproteinases (TIMPs). TIMPs offer an unparalleled scaffold for developing new MMP inhibitors of novel selectivity.

Unlike synthetic MMP inhibitors, tissue inhibitors of metalloproteinases feature a broad and extensive contact surface for interaction with MMP targets, encompassing more than 20 amino acid residues. This large interface offers an outstanding opportunity for molecular optimization.

Using both structure-guided approaches and directed evolution techniques, Dr. Radisky's Proteases in Cancer Laboratory and several collaborating laboratories are exploring the idea that TIMPs, like antibodies, can be engineered as targeted protein therapeutics of remarkable affinity and exquisite selectivity.

Dr. Radisky's research team is working to develop selective inhibitors for several MMPs known to promote cancer progression by modifying the natural human TIMPs. These include MMP-3, a key inducer of epithelial-mesenchymal transition (EMT) and tumor progression in lung and breast cancers; MMP-10, an enzyme necessary for lung tumors for maintenance of the cancer stem cell phenotype; and MMP-9, a critical inducer of EMT, invasion, metastasis and angiogenesis in breast cancer and many other tumor types.

Related publications

Dr. Radisky's research publications on defining and engineering specificity of tissue inhibitors of metalloproteinases include: