Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites

Publication

Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites

Journal Paper/Review - Jan 28, 2013

Geurink Paul P, Overkleeft Herman S, Groll Michael, van der Stelt Mario, Driessen Christoph, van der Marel Gijs A, Florea Bogdan I, Mock Elliot D, Voges Mathias J, Blom Annet E M, de Bruin Gerjan, Gallastegui Nerea, Mirabella Anne C, van der Linden Wouter A, Kisselev Alexei F

Citation

Geurink P, Overkleeft H, Groll M, van der Stelt M, Driessen C, van der Marel G, Florea B, Mock E, Voges M, Blom A, de Bruin G, Gallastegui N, Mirabella A, van der Linden W, Kisselev A. Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites. J Med Chem 2013; 56:1262-75.

Type

Journal Paper/Review (English)

Journal

J Med Chem 2013; 56

Publication Date

Jan 28, 2013

Issn Electronic

1520-4804

Pages

1262-75

Brief description/objective

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.