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Incorporation of fluorinated phenylalanine generates highly specific inhibitor of proteasome's chymotrypsin-like sites.

ABSTRACT: Proteasomal processing is conducted by three individual catalytic subunits, namely beta1, beta2, and beta5. Subunit-specific inhibitors are useful tools in dissecting the role of these individual subunits and are leads toward the development of antitumor agents. We here report that the presence of fluorinated phenylalanine derivatives in peptide based proteasome inhibitors has a profound effect on inhibitor potency and selectivity. Specifically, compound 4a emerges as one of the most beta5 specific inhibitors known to date.

SUBMITTER: Geurink PP

PROVIDER: S-EPMC3037272 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Incorporation of fluorinated phenylalanine generates highly specific inhibitor of proteasome's chymotrypsin-like sites.

Geurink Paul P PP Liu Nora N Spaans Michiel P MP Downey Sondra L SL van den Nieuwendijk Adrianus M C H AM van der Marel Gijsbert A GA Kisselev Alexei F AF Florea Bogdan I BI Overkleeft Herman S HS

Journal of medicinal chemistry 20100301 5

Proteasomal processing is conducted by three individual catalytic subunits, namely beta1, beta2, and beta5. Subunit-specific inhibitors are useful tools in dissecting the role of these individual subunits and are leads toward the development of antitumor agents. We here report that the presence of fluorinated phenylalanine derivatives in peptide based proteasome inhibitors has a profound effect on inhibitor potency and selectivity. Specifically, compound 4a emerges as one of the most beta5 speci ...[more]

PMID: 20131905

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