Cathepsin B, a cysteine protease, has emerged as a potential therapeutic target due to its aberrant role in plethora of diseases including cancer. Currently, active-site targeting non-peptidyl small molecule inhibitors of cathepsins remain scarcely available. In this study, a series of sulfonyloxiranes are synthesized and evaluated as inhibitors of cysteine cathepsins. 2-(2-ethylphenylsulfonyl)oxirane is identified as a potent and specific inhibitor of Cysteine cathepsin B. Kinetic analysis suggests that 2-(2-ethylphenylsulfonyl)oxirane is an active-site directed, covalent and irreversible inhibitor. This has been further confirmed by mass spectrometric analysis of the inhibited complex of 2-(2-ethylphenylsulfonyl)oxirane with Cathepsin B. A molecular modeling study of the covalently-modified complex of 2-(2-ethylphenylsulfonyl)oxirane with Cathepsin B reveals a favorable interaction of 2-(2-ethylphenylsulfonyl)oxirane with many key active site residues. Finally, cell-based experiments on metastatic breast cancer cell line indicates that 2-(2-ethylphenylsulfonyl)oxirane is cell permeable with anti-metastatic potential, and inhibits cysteine cathepsin B activity in a dose dependent manner.

Development of small molecule inhibitors of cathepsin B as antimetastatic agents

245th National Meeting (2013)

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