title: Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.
abstract: We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors: Zachary
authors: Z
authors: Miller
authors: Keun-Sik
authors: KS
authors: Kim
authors: Do-Min
authors: DM
authors: Lee
authors: Vinod
authors: V
authors: Kasam
authors: Si Eun
authors: SE
authors: Baek
authors: Kwang Hyun
authors: KH
authors: Lee
authors: Yan-Yan
authors: YY
authors: Zhang
authors: Lin
authors: L
authors: Ao
authors: Kimberly
authors: K
authors: Carmony
authors: Na-Ra
authors: NR
authors: Lee
authors: Shou
authors: S
authors: Zhou
authors: Qingquan
authors: Q
authors: Zhao
authors: Yujin
authors: Y
authors: Jang
authors: Hyun-Young
authors: HY
authors: Jeong
authors: Chang-Guo
authors: CG
authors: Zhan
authors: Wooin
authors: W
authors: Lee
authors: Dong-Eun
authors: DE
authors: Kim
authors: Kyung Bo
authors: KB
authors: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D011720:Pyrazoles; D054852:Small Molecule Libraries; C031280:pyrazole; D046988:Proteasome Endopeptidase Complex