A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids.
Basic Information
ID: ALA4020701
Journal: Bioorg Med Chem
Title: A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids.
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.
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.
CiteXplore: 28236510
DOI: 10.1016/j.bmc.2017.01.020
Patent ID: ┄