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A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids.

Abstract：

:The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, β-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Zhu M,Harshbarger WD,Robles O,Krysiak J,Hull KG,Cho SW,Richardson RD,Yang Y,Garcia A,Spiegelman L,Ramirez B,Wilson CT,Yau JA,Moore JT,Walker CB,Sacchettini JC,Liu WR,Sieber SA,Smith JW,Romo D

doi

10.1016/j.bmc.2017.01.020

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

2901-2916

issue

11

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)31267-6

journal_volume

25

pub_type

杂志文章

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