Proteases in Cancer - Evette S. Radisky

Project 2: Defining and engineering specificity of tissue inhibitor of metalloproteinases-1 (TIMP-1)

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 MMP inhibitor development could be the engineering of naturally occurring protein inhibitors of MMPs — the tissue inhibitors of metalloproteinases (TIMPs). The Proteases in Cancer Laboratory is working to develop selective inhibitors for several MMPs known to promote cancer progression by modifying the natural human protein TIMP-1.

TIMPs, natural protein inhibitors that regulate matrix metalloproteinase (MMP) activity in the body, offer an unparalleled scaffold for developing new MMP inhibitors of novel selectivity. Unlike synthetic MMP inhibitors, TIMPs feature a broad and extensive contact surface for interaction with MMP targets, encompassing more than 20 amino acid residues.

Reminiscent of antibody complementarity-determining regions (CDRs), the TIMP binding inter-face comprises six discontinuous amino acid segments spread over two protein domains, which pack together to present the MMP-binding surface. This large interface offers an outstanding opportunity for molecular optimization.

Using both structure-guided approaches and directed evolution techniques, the Radisky Proteases in Cancer Laboratory is exploring the idea that TIMPs, like antibodies, may be engineered as targeted protein therapeutics of remarkable affinity and exquisite selectivity. The Proteases in Cancer lab is pursuing selective inhibitors of 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

• Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: binding studies and crystal structure
• Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression
• Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential
• Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer

Image gallery

TIMP-1 protein scaffold

TIMP-1/MMP-10 complex

Central TIMP-1