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

作者：Zhu Mingzhao; Harshbarger Wayne D; Robles Omar; Krysiak Joanna; Hull Kenneth G; Cho Sung Wook; Richardson Robyn D; Yang Yanyan; Garcia Andres; Spiegelman Lindsey; Ramirez Bianca; Wilson Christopher T; Yau Ju Anne; Moore James T; Walker Caitlen B; Sacchettini James C; Liu Wenshe R; Sieber Stephan A; Smith Jeffrey W; Romo Daniel^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(11): 2901-2916.

DOI：10.1016/j.bmc.2017.01.020

• Beta-lactones
• Inhibitor
• Activity-based protein profiling
• Structure-activity relationship studies
• Serum stability

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, B-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.

• 出版日期2017-6-1