title: Syrbactin Structural Analog TIR-199 Blocks Proteasome Activity and Induces Tumor Cell Death.
abstract: Multiple myeloma is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade®), carfilzomib (Kyprolis®), and ixazomib (Ninlaro®), confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory multiple myeloma and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog. Molecular modeling and simulation suggested that TIR-199 covalently binds each of the three catalytic subunits (β1, β2, and β5) and revealed key interaction sites. In vitro and cell culture-based proteasome activity measurements confirmed that TIR-199 inhibits the proteasome in a dose-dependent manner and induces tumor cell death in multiple myeloma and neuroblastoma cells as well as other cancer types in the NCI-60 cell panel. It is particularly effective against kidney tumor cell lines, with >250-fold higher anti-tumor activities than observed with the natural product syringolin A. In vivo studies in mice revealed a maximum tolerated dose of TIR-199 at 25 mg/kg. The anti-tumor activity of TIR-199 was confirmed in hollow fiber assays in mice. Adverse drug reaction screens in a kidney panel revealed no off-targets of concern. This is the first study to examine the efficacy of a syrbactin in animals. Taken together, the results suggest that TIR-199 is a potent new proteasome inhibitor with promise for further development into a clinical drug for the treatment of multiple myeloma and other forms of cancer.
authors.affiliation: From the Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, the Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii, Hilo, Hawaii 96720, the Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii 96822, andre.bachmann@hc.msu.edu.
authors.forename: André S
authors.initials: AS
authors.lastname: Bachmann
authors.affiliation: the Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii, Hilo, Hawaii 96720.
authors.forename: John
authors.initials: J
authors.lastname: Opoku-Ansah
authors.affiliation: the Department of Chemistry, University of California, Riverside, California 92521, and.
authors.forename: Tannya R
authors.initials: TR
authors.lastname: Ibarra-Rivera
authors.affiliation: From the Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503, the Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii, Hilo, Hawaii 96720, the Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii 96822.
authors.forename: Lisette P
authors.initials: LP
authors.lastname: Yco
authors.affiliation: the Department of Chemistry, University of California, Riverside, California 92521, and.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Ambadi
authors.affiliation: the Department of Chemistry, University of California, Riverside, California 92521, and.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Roberts
authors.affiliation: the Department of Chemistry, University of California, Riverside, California 92521, and.
authors.forename: Chia-En A
authors.initials: CE
authors.lastname: Chang
authors.affiliation: the Department of Chemistry, University of California, Riverside, California 92521, and the Department of Pharmaceutical Sciences, University of California, Irvine, California 92697 Michael.pirrung@ucr.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Pirrung
mesh_terms: D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: TIR-199; anti-tumor activity; chemical synthesis; computer modeling; hollow fiber assays; multiple myeloma; natural product; neuroblastoma; proteasome; syringolin A