A Strategy for Dual Inhibition of the Proteasome and Fatty Acid Synthase with Belactosin C-Orlistat Hybrids

Publication date: Available online 19 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Mingzhao Zhu, Wayne D. Harshbarger, Omar Robles, Joanna Krysiak, Kenneth G. Hull, Sung Wook Cho, Robyn D. Richardson, Yanyan Yang, Andres Garcia, Lindsey Spiegelman, Bianca Ramirez, Christopher T. Wilson, Ju Anne Yau, James T. Moore, Caitlen B. Walker, James C. Sacchettini, Wenshe Liu, Stephan A. Sieber, Jeffrey W. Smith, Daniel Romo
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 FAS-TE enabling a new approach for the development of drug-candidates with potential to overcome resistance.

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