title: Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites.
abstract: Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that combinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antineoplastic activity than combinations currently used clinically.
authors: Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors: Paul P
authors: PP
authors: Geurink
authors: Wouter A
authors: WA
authors: van der Linden
authors: Anne C
authors: AC
authors: Mirabella
authors: Nerea
authors: N
authors: Gallastegui
authors: Gerjan
authors: G
authors: de Bruin
authors: Annet E M
authors: AE
authors: Blom
authors: Mathias J
authors: MJ
authors: Voges
authors: Elliot D
authors: ED
authors: Mock
authors: Bogdan I
authors: BI
authors: Florea
authors: Gijs A
authors: GA
authors: van der Marel
authors: Christoph
authors: C
authors: Driessen
authors: Mario
authors: M
authors: van der Stelt
authors: Michael
authors: M
authors: Groll
authors: Herman S
authors: HS
authors: Overkleeft
authors: Alexei F
authors: AF
authors: Kisselev
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002460:Cell Line; D002463:Cell Membrane Permeability; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D061988:Proteasome Inhibitors / Q000737:chemistry*; D014357:Trypsin / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D061988:Proteasome Inhibitors; D014357:Trypsin