The proteasome inhibitors bortezomib and carfilzomib have effectively revolutionized the treatment of multiple myeloma over the past decade. Unfortunately, despite many preclinical indications of activity and multiple clinical trials, these first-generation agents have proven relatively ineffective in solid cancers. We hypothesize that this poor in vivo activity stems from multiple limitations of bortezomib and carfilzomib including rapid metabolism, susceptibility to efflux transporters, and undesired off-target activities. We further believe that these limitations stem from common structural and functional characteristics: peptide-based structures and the use of reactive electrophilic warheads to mediate inhibition. Accordingly, we sought to develop novel proteasome inhibitors which were non-peptide in structure and did not rely on covalent bonding to mediate proteasome inhibition. We began with a thorough in silico screen of more than 340,000 structures and via in vitro screening we identified a 1,3,5-substituted pyrazole compound with potent in vitro activity and potent cytotoxic activity in cellulo. We have since explored the structure-activity relationship of this scaffold through the synthesis and testing of over 40 analogs and we have demonstrated that our lead compound is active in vivo in a mouse xenograft model of prostate cancer with no observed toxicity. We have also shown that these compounds act as reversible inhibitors and appear to be highly metabolically stable in vitro. Further preclinical development including experiments to validate the proteasome as the biological target of these inhibitors and efforts to identify any potential off-target activities of our lead compound are currently under way. We are also working to develop inhibitors with greater potency and improved physiochemical properties in the hopes of creating non-peptide proteasome inhibitors suitable for use in humans. It is our belief that the development of such a proteasome inhibitor with the correct pharmacokinetic and pharmacodynamics properties could prove to be a highly useful cancer therapy.

Development of non-peptide pyrazole-based proteasome inhibitors as anticancer agents

248th National Meeting (2014)

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