Incorporation of fluorinated phenylalanine generates highly specific inhibitor of proteasome's chymotrypsin-like sites.
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.
Leiden Institute of Chemistry and Netherlands Proteomics Centre, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Paul P
PP
Geurink
Nora
N
Liu
Michiel P
MP
Spaans
Sondra L
SL
Downey
Adrianus M C H
AM
van den Nieuwendijk
Gijsbert A
GA
van der Marel
Alexei F
AF
Kisselev
Bogdan I
BI
Florea
Herman S
HS
Overkleeft
D020134:Catalytic Domain / Q000187:drug effects*; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D010649:Phenylalanine; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex