Syringolin A selectively labels the 20 S proteasome in murine EL4 and wild-type and bortezomib-adapted leukaemic cell lines.
The natural product syringolin A (SylA) is a potent proteasome inhibitor with promising anticancer activities. To further investigate its potential as a lead structure, selectivity profiling with cell lysates was performed. At therapeutic concentrations, a rhodamine-tagged SylA derivative selectively bound to the 20 S proteasome active sites without detectable off-target labelling. Additional profiling with lysates of wild-type and bortezomib-adapted leukaemic cell lines demonstrated the retention of this proteasome target and subsite selectivity as well as potency even in clinically relevant cell lines. Our studies, therefore, propose that further development of SylA might indeed result in an improved small molecule for the treatment of leukaemia.
Clerc
Jérôme
J
Chemical Genomics Centre der Max-Planck-Gesellschaft, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Florea
Bogdan I
BI
Kraus
Marianne
M
Groll
Michael
M
Huber
Robert
R
Bachmann
André S
AS
Dudler
Robert
R
Driessen
Christoph
C
Overkleeft
Herman S
HS
Kaiser
Markus
M
D000818:Animals; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D007942:Leukemia, Experimental / Q000201:enzymology / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage*; D021241:Spectrometry, Mass, Electrospray Ionization
D001897:Boronic Acids; D010456:Peptides, Cyclic; D011719:Pyrazines; C407267:syringolin A; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex