Onyx Therapeutics, Inc.

Proteolix, Inc.

Rigel Pharmaceuticals, Incorporated

Onyx Technologies, Inc.

Guy J Laidig

Mark Stephen Smyth

Kevin D Shenk

Han-Jie Zhou

Catherine Sylvain

Mark K Bennett

Francesco Parlati

Congcong M Sun

John H Musser

Craig M Crews

Ronald T Borchardt

Barry A Bunin

William D Fuller

Pasit Phiasivongsa

Louis C Sehl

Rajinder Paul Singh

Sambaiah Thota

Henry Lu

Peggy A Radel

William Dean Fuller

John Clifford Chabala

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases associated with the proteasome. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation. Oral administration of these peptide-based proteasome inhibitors is possible due to their bioavailability profiles.

Compounds for enzyme inhibition

One aspect of the invention relates to inhibitors that preferentially inhibit immunoproteasome activity over constitutive proteasome activity. In certain embodiments, the invention relates to the treatment of immune related diseases, comprising administering a compound of the invention. In certain embodiments, the invention relates to the treatment of cancer, comprising administering a compound of the invention.

The invention relates to crystalline peptide keto epoxide compounds, methods of their preparation, and related pharmaceutical compositions. This invention also relates to methods for the preparation of amino acid keto-epoxides. Specifically, allylic ketones are stereoselectively converted to the desired keto epoxides.

Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

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Menlo Park, CA, United States of America

Guy J Laidig