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3028  J. Med. Chem. 2009, 52, 3028–3038  Design and Synthesis of an Orally Bioavailable and Selective Peptide Epoxyketone Proteasome Inhibitor (PR-047) Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and Non-Hodgkin’s lymphoma. Car?lzomib, an epoxyketone currently undergoing clinical trials in malignant diseases, is a highly selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. A chemistry effort was initiated to discover orally bioavailable analogues of car?lzomib, which would have potential for improved dosing ?exibility and patient convenience over intravenously administered agents. The lead compound, 2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide (58) (PR-047), selectively inhibited CT-L activity of both the constitutive proteasome ( 5) and immunoproteasome (LMP7) and demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It was well tolerated with repeated oral administration at doses resulting in 80% proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered car?lzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic pro?le supports its further development for the treatment of malignant diseases.  Introduction The proteasome is a multicatalytic protease complex that is responsible for the ubiquitin-dependent turnover of cellular proteins.1-3 Proteasome substrates include misfolded or mis- assembled proteins as well as short-lived components of signaling cascades that regulate cell proliferation and survival pathways. Inhibition of the proteasome leads to an accumulation of substrate proteins and results in cell death.4 The proteasome consists of a 20S proteolytic core and two 19S regulatory caps that assemble with the core at either end to form a 26S complex.5,6 Two distinct forms of the 26S proteasome, the constitutive proteasome and the immunoproteasome, ha