In the search for cancer chemotherapy options, the 20S proteasome has become a target of interest. The natural product TMC-95A is a macrocyclic peptide that has been found to inhibit the proteasome non-covalently through hydrogen bonding. We have designed a new class of modified TMC-95A analogs that include a biaryl ether macrocycle as well as a C-terminal aldehyde that binds to the catalytic nucleophile in the enzyme active site. An SAR study was performed to determine the optimal peptide sequence. It was found that whereas a central leucine residue is most potent in inhibiting the chymotrypsin-like activity, a central asparagine residue is more effective in targeting all three catalytic activities simultaneously.

SAR of macrocyclic TMC-95A analogs as inhibitors of the proteasome

245th National Meeting (2013)

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