Proteases as Anti-Cancer Targets - Molecular and Biological Basis for Development of Inhibitor-Like Drugs Against Cancer

A.      Bialas; P.      Kafarski

doi:10.2174/187152009789056877

Abstract

The systematic improvement of methods used for unraveling physiological and pathological role of proteases, as well as for elucidation of relevant hydrolase structures contributes to the progress in the area of new inhibitor-like drugs development. Many of protease inhibitors have entered clinics and are now successfully applied for the treatment of various systemic disorders caused by deregulation of physiological processes governed by proteolytic enzymes, including cardiovascular, neurodegenerative and inflammatory diseases. A clinical approach based on targeting of proteases involved in pathomechanism of given diseases also stimulates the interest as anti-cancer strategy alternative, or supplementary, to surgical intervention and radiotherapy. In this survey we present some current achievements on the field of development of protease inhibitors designed as potential anti-cancer drugs and/or tools for studying molecular basis of processes associated with the cancer development and spread. Our intention is to show the results of this research in context of the structure-activity relationship (SAR) studies, which explain inhibitor requirements of the target proteases. We also provide the examples of attempts being made to eliminate drawbacks of the earlier-developed inhibitors (e.g. such as low selectivity or poor pharmacological profile arising from their peptide-like character). Moreover, modern approach to protease targets recognition by means of socalled activity-based protein profiling as well as new ‘fail-off’ methodology of in vivo inhibitor screening, which provide structures potent both in vitro and under physiological conditions are also described. At last, an example proving usefulness of high throughput screening as method for selection of the non-peptidic leads for protease inhibitors can be found in this article.

Keywords: Proteases, Inhibitors, Anti-cancer, Mechanism-based, uPA, Matriptase, MMPs, Cathepsins, Proteasome, Selectivity