A new structural class of selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome

Bioorganic and Medicinal Chemistry Letters

Volumn 11, Issue 10, 2001, Pages 1317-1319

  Garcia Echeverria C ^a   Imbach, P ^a   France, D ^a   Furst P ^a   Lang, M ^a   Noorani, M ^a   Scholz, D ^b   Zimmermann, J ^a   Furet, P ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

^b NOVARTIS RESEARCH INSTITUTE   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINOBENZYLSTATINE DERIVATIVE; 20S PROTEASOME; CHYMOTRYPSIN; PROTEASOME; STATINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL MODIFICATION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; HUMAN; IN VITRO STUDY;

AMINO ACIDS; ANTI-INFLAMMATORY AGENTS; ANTINEOPLASTIC AGENTS; CHYMOTRYPSIN; CYSTEINE ENDOPEPTIDASES; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MULTIENZYME COMPLEXES; OLIGOPEPTIDES; PEPTIDE LIBRARY; PROTEASOME ENDOPEPTIDASE COMPLEX; PROTEIN BINDING; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0035927193     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(01)00205-0     Document Type: Article

References (25)

1. Tanaka K. J. Biochem. 123:1998;195.
2. Orlowski M., Cardozo C., Michaud C. Biochemistry. 32:1993;1563.
3. Tanaka K., Kasahara M. Immunol. Rev. 163:1998;161.
4. Goldberg A.L., Akopian T.N., Kisselev A.F., Lee D.H., Rohrwild M. Biol. Chem. 378:1997;131.
5. King R.W., Deshaies R.J., Peters J.-M., Kirschner M.W. Science. 274:1996;1652.
6. Palombela V.J., Rando O.J., Goldberg A.L., Mainatis T. Cell. 78:1994;773.
7. For recent reviews on this target and 20S proteasome inhibitors, see: Rivett A.J., Gardner R.C. J. Pept. Sci. 6:2000;478.
8. Dou Q.P., Nam S. Expert Opin. Ther. Pat. 10:2000;1263.
9. Adams J., Palombella V.J., Elliott P.J. Invest. New Drugs. 18:2000;109.
10. Murray R.Z., Norbury C. Anti-Cancer Drugs. 11:2000;407.
11. Dou Q.P., Li B. Drug Resist. Updates. 2:1999;215.
12. Elliott P.J., Adams J. Curr. Opin. Drug. Disc. Dev. 2:1999;484.
13. Kalogeris T., Gray L., Laroux F.S., Cockrell A., Fuseler J., Conner E.M., Brand S., Grisham M.B. Expert Opin. Invest. Drugs. 8:1999;1397.
14. Lee D.H., Goldberg A.L. Trends Cell Biol. 8:1998;397.
15. A dipeptide boronic acid analogue (PS-341) is currently under clinical evaluation in advanced cancer patients. For additional data on this compound, see: Adams J., Palombella V.J., Sausville E.A., Johnson J., Destree A., Lazarus D.D., Maas J., Pien C.S., Prakash S., Elliott P.J. Cancer Res. 59:1999;2615.
16. To date, several classes of 20S proteasome inhibitors have been described: peptide aldehydes, peptide α-keto aldehydes (glyoxals), peptide α′,β′-epoxyketones, peptide vinyl sulfones, peptide indanones, peptide boronic acids (e.g., PS-341, see ref 5), bifunctional inhibitors or natural products (e.g., lactacystin, epoxomicin, TMC-95A-D or UCK 14A2); see also ref 4.
17. Billich A., Scholz D., Charpiot B., Gstach H., Lehr P., Peichi P., Rosenwirth B. Antiviral Chem. Chemother. 6:1995;327.
18. Lehr P., Billich A., Charpiot B., Ettmayer P., Scholz D., Rosenwirth B., Gstach H. J. Med. Chem. 39:1996;2060.
19. Scholz D., Billich A., Charpiot B., Ettmayer P., Lehr P., Rosenwirth B., Schreiner E., Gstach H. J. Med. Chem. 37:1994;3079.
20. The human placenta 20S proteasome was obtained from Diabetes Forschungsinstitut, Düsseldorf, Germany.
21. Compound 1 was identified during the high-throughput screening of our entire in-house compound collection.
22. Other inhibitors of the HIV-1 protease have been described as inhibitors of the 20S proteasome: (a) Andre, P.; Lotteau, V.; Zinkernagel, R.; Klenerman, P.; Groettrup, M. WO 9963998, 1999.
23. Andre P., Groettrup M., Klenerman P., de Giuli R., Booth B.L. Jr., Cerundolo V., Bonneville M., Jotereau F., Zinkernagel R.M., Lotteau V. Proc. Natl. Acad. Sci. U.S.A. 95:1998;13120.
24. The active site of the chymotrypsin-type activity of the human 20S proteasome is formed by the association of these two β-subunits.
25. The N-terminal building blocks were determined by molecular modeling on the basis of our binding model for this structural class of compounds (Furet, P.; Imbach, P.; Fürst, P.; Lang, M.; Noorani, M.; Zimmermann, J.; García-Echeverría, C. Bioorg. Med. Chem. Lett. 2001, 11, 1321).