title: Inhibition of the human proteasome by imidazoline scaffolds.
abstract: The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.
authors.affiliation: Department of Chemistry, Michigan State University , East Lansing, Michigan 48824, United States.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Azevedo
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Lansdell
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Ludwig
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mosey
authors.forename: Daljinder K
authors.initials: DK
authors.lastname: Woloch
authors.forename: Dillon P
authors.initials: DP
authors.lastname: Cogan
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Patten
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kuszpit
authors.forename: Jason S
authors.initials: JS
authors.lastname: Fisk
authors.forename: Jetze J
authors.initials: JJ
authors.lastname: Tepe
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002460:Cell Line; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D048288:Imidazolines; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib