Document Report Card

ID: ALA1138457

Journal: J Med Chem

Title: Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047).

Authors: Zhou HJ, Aujay MA, Bennett MK, Dajee M, Demo SD, Fang Y, Ho MN, Jiang J, Kirk CJ, Laidig GJ, Lewis ER, Lu Y, Muchamuel T, Parlati F, Ring E, Shenk KD, Shields J, Shwonek PJ, Stanton T, Sun CM, Sylvain C, Woo TM, Yang J.

Abstract: Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and non-Hodgkin's lymphoma. Carfilzomib, 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 carfilzomib, which would have potential for improved dosing flexibility 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 (beta5) 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 carfilzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic profile supports its further development for the treatment of malignant diseases.

CiteXplore: 19348473

DOI: 10.1021/jm801329v