The ubiquitin/proteasome pathway is the primary means by which intracellular protein degradation occurs.  As such, the proteasome plays a central role in regulating most facets of cell physiology and has been the target of drug discovery programs in cancer and inflammatory diseases.  Cleavage of target proteins occurs via 3 distinct proteolytic activities within the 20S core particle of the 26S proteasome. There are 2 forms of the 20S core, the constitutive proteasome and the immunoproteasome, distinguished by their active site subunits.  These active sites, defined in part by their substrate specificity, make up a unique class of proteases in that the catalytic nucleophile is an N-terminal threonine residue.  Several distinct classes of proteasome inhibitors have been described, with multiple compounds having entered clinical trials, and 2 drugs, bortezomib (a peptide boronate) and carfilzomib (a peptide epoxyketone), achieving marketing approval for the treatment of multiple myeloma.  Peptide epoxyketones are distinguished by formation of a dual-covalent, morpholino adduct formed by reaction with the side chain hydroxyl and free amine of the catalytic threonine.   This distinct chemical mechanism has enabled improved selectivity against other classes of proteases.   The resulting elimination of off-target activity enabled the exploration of dose intensive therapy with carfilzomib in clinical trials, which translated to increased response rates and activity in patients resistant to bortezomib.  Through a pharmacology driven medicinal chemistry effort, we designed an orally bioavailable analog of carfilzomib, oprozomib, which displays similar levels of proteasome inhibition and biodistribution.   Another focus of our research is subunit selective inhibitors.  Our discovery of  subunit selective peptide epoxyketones  has helped elucidate distinct roles for both the immunoproteasome and constitutive proteasome in immune cell biology.  Immunoproteasome selective inhibitors are highly efficacious in mouse models of autoimmunity and represent a new class of therapeutics for the treatment of inflammatory diseases.

Towards optimized utility of proteasome inhibitors with peptide epoxyketones

245th National Meeting (2013)

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