Title: Abstract 5069: Engineering TIMP-1 for selective MMP inhibition and future use as a protein therapeutic.
Abstract: Abstract Matrix metalloproteinases (MMPs), a family of extracellular matrix degrading proteins, have been found to be upregulated in many human cancers and have been shown to contribute to cancer progression. There have been many aborted attempts to target MMPs therapeutically using small molecule inhibitors; the limited selectivity of most MMP inhibitors may be a major factor contributing to their poor effectiveness. As an alternative to small molecule MMP inhibitors, we are developing new methodology to create selective protein inhibitors of MMPs, based on the scaffold of the natural inhibitor TIMP-1, that may be used as protein therapeutics. Because TIMP-1 has a very short plasma half-life, we have developed methods for PEGylation that extend the plasma half-life to about 24h while preserving MMP inhibitory activity, rendering it more suitable for in vivo applications. We have also generated mutations in TIMP-1 that confer selective binding toward particular MMPs. The targets thus far pursued include MMP-9, MMP-3, and MMP-10, which represent therapeutic targets of interest in breast cancer and lung cancer. In the future, the methods developed here can be used to identify TIMP-1 variants selective toward additional MMPs, which may be of utility in the research and treatment of many human cancers. Citation Format: Christine Mehner, Jyotica Batra, Jessica Robinson, Derek C. Radisky, Evette S. Radisky. Engineering TIMP-1 for selective MMP inhibition and future use as a protein therapeutic. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5069. doi:10.1158/1538-7445.AM2013-5069
Publication Year: 2013
Publication Date: 2013-04-01
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 1
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