Evaluation of new synthetic cathepsin D inhibitors

Cathepsin D (CatD) is a ubiquitous aspartic protease found in all higher organisms and expressed in nearly all human tissues. Because it is associated with the mobility and invasiveness of various cancers, inhibitors of this enzyme have the potential for use as cancer research tools and possibly as chemotherapeutic drugs. New tripeptide analogues have been synthesized and were evaluated for their inhibition of CatD. Eight new potential inhibitors were screened for inhibition of human CatD. Of these, four were found to be strong inhibitors of the enzyme, and these four were analyzed to determine their IC50 values. These four inhibitors, as well as four inhibitors screened previously, were analyzed for their kinetic parameters, dissociation constants and inhibition mode. These studies were performed using purified human cathepsin D and a fluorogenic substrate. Several of the compounds were found to be strong inhibitors of cathepsin D, with IC50 values in the nanomolar range.