Anticancer Agents Based on a New Class of Transition-State Analog Inhibitors for Serine and Cysteine Proteases

摘要

In this Final Report we describe our efforts over the last four years to develop a new class of competitive inhibitors for serine and cysteine proteases. These compounds are potential anticancer agents that would act by inhibiting metastasis and angiogenesis. Our work has shown that the 4- heterocyclohexanone pharmacophore can be used to synthesize effective inhibitors of both serine and cysteine proteases. We have rationally designed an inhibitor of the serine protease plasmin, and shown that it has good activity and specificity for plasmin over other proteases. In addition, we have used the 4- heterocyclohexanone pharmacophore to construct a combinatorial library of 400 different protease inhibitors. These compounds are unique in that they are designed to interact with both the S and S' binding sites of proteases; a feature which will increase both their potency and specificity. The library was screened against a variety of cancer-related proteases, which lead us to identify a second, even more potent inhibitor of plasmin. Finally, our investigations into the mechanism of action of these inhibitors has shown that 4-heterocyclohexanones inhibit the proteases be reacting in a reversible covalent manner with the active site nucleophile of the enzymes.