title: 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.
authors.affiliation: Department of Chemistry & Biochemistry and CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX 76706, USA.
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Harshbarger
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Robles
authors.affiliation: Department of Chemistry, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Krysiak
authors.affiliation: Department of Chemistry & Biochemistry and CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX 76706, USA.
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Hull
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Cho
authors.affiliation: Sanford Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Robyn D
authors.initials: RD
authors.lastname: Richardson
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Garcia
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Spiegelman
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Bianca
authors.initials: B
authors.lastname: Ramirez
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Wilson
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Ju Anne
authors.initials: JA
authors.lastname: Yau
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Moore
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Caitlen B
authors.initials: CB
authors.lastname: Walker
authors.affiliation: Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77840, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
authors.forename: Wenshe R
authors.initials: WR
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
authors.affiliation: Sanford Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Smith
authors.affiliation: Department of Chemistry & Biochemistry and CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX 76706, USA. Electronic address: Daniel_Romo@baylor.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Romo
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D015394:Molecular Structure; D000077403:Orlistat; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007783:Lactones; D010455:Peptides; C406054:belactosin C; D000077403:Orlistat; D064429:Fatty Acid Synthases; D046988:Proteasome Endopeptidase Complex
keywords: Activity-based protein profiling; Beta-lactones; Inhibitor; Serum stability; Structure-activity relationship studies