Title:
COMPOUNDS FOR PROTEASOME ENZYME INHIBITION
Document Type and Number:
WIPO Patent Application WO2005105827
Kind Code:
A3
Abstract:
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.
Inventors:
SMYTH MARK S (US)
LAIDIG GUY J (US)
BORCHARDT RONALD T (US)
BUNIN BARRY A (US)
CREWS CRAIG M (US)
MUSSER JOHN H (US)
SCHNEEKLOTH JOHN S JR (US)
CHABALA JOHN CLIFFORD (US)
LAIDIG GUY J (US)
BORCHARDT RONALD T (US)
BUNIN BARRY A (US)
CREWS CRAIG M (US)
MUSSER JOHN H (US)
SCHNEEKLOTH JOHN S JR (US)
CHABALA JOHN CLIFFORD (US)
Application Number:
PCT/US2005/012740
Publication Date:
March 30, 2006
Filing Date:
April 14, 2005
Export Citation:
Assignee:
PROTEOLIX INC (US)
SMYTH MARK S (US)
LAIDIG GUY J (US)
BORCHARDT RONALD T (US)
BUNIN BARRY A (US)
CREWS CRAIG M (US)
MUSSER JOHN H (US)
SCHNEEKLOTH JOHN S JR (US)
CHABALA JOHN CLIFFORD (US)
SMYTH MARK S (US)
LAIDIG GUY J (US)
BORCHARDT RONALD T (US)
BUNIN BARRY A (US)
CREWS CRAIG M (US)
MUSSER JOHN H (US)
SCHNEEKLOTH JOHN S JR (US)
CHABALA JOHN CLIFFORD (US)
International Classes:
A61K38/06; C07K5/087; C07K5/08
Domestic Patent References:
| WO2001028579A2 | 2001-04-26 |
Foreign References:
| US6831099B1 | 2004-12-14 |
Other References:
ELOFSSON M ET AL: "TOWARDS SUBUNIT-SPECIFIC PROTEASOME INHIBITORS: SYNTHESIS AND EVALUATION OF PEPTIDE ALPHA',BETA'-EPOXYKETONES", CHEMISTRY AND BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 6, no. 11, 1995, pages 811 - 822, XP001002198, ISSN: 1074-5521
MYUNG J ET AL: "Lack of proteasome active site allostery as revealed by subunit-specific inhibitors.", MOLECULAR CELL. FEB 2001, vol. 7, no. 2, February 2001 (2001-02-01), pages 411 - 420, XP002342741, ISSN: 1097-2765
MYUNG J ET AL: "THE UBIQUITIN-PROTEASOME PATHWAY AND PROTEASOME INHIBITORS", MEDICINAL RESEARCH REVIEWS, NEW YORK, NY, US, vol. 21, no. 4, July 2001 (2001-07-01), pages 245 - 273, XP001029647, ISSN: 0198-6325
KIM K B ET AL: "Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. 6 DEC 1999, vol. 9, no. 23, 6 December 1999 (1999-12-06), pages 3335 - 3340, XP004183734, ISSN: 0960-894X
MYUNG J ET AL: "Lack of proteasome active site allostery as revealed by subunit-specific inhibitors.", MOLECULAR CELL. FEB 2001, vol. 7, no. 2, February 2001 (2001-02-01), pages 411 - 420, XP002342741, ISSN: 1097-2765
MYUNG J ET AL: "THE UBIQUITIN-PROTEASOME PATHWAY AND PROTEASOME INHIBITORS", MEDICINAL RESEARCH REVIEWS, NEW YORK, NY, US, vol. 21, no. 4, July 2001 (2001-07-01), pages 245 - 273, XP001029647, ISSN: 0198-6325
KIM K B ET AL: "Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. 6 DEC 1999, vol. 9, no. 23, 6 December 1999 (1999-12-06), pages 3335 - 3340, XP004183734, ISSN: 0960-894X
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