title: Inhibiting aberrant signal transducer and activator of transcription protein activation with tetrapodal, small molecule Src homology 2 domain binders: promising agents against multiple myeloma.
abstract: The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes. In particular, Stat3 protein has attracted attention as it regulates the expression of genes involved in a variety of malignant processes, including proliferation, survival, migration, and drug resistance. Multiple myeloma (MM) is an incurable hematologic malignancy that often exhibits abnormally high levels of Stat3 activity. Although current treatment strategies can improve the clinical management of MM, it remains uniformly incurable with a dismal median survival time post-treatment of 3-4 years. Thus, novel targeted therapeutics are critically needed to improve MM patient outcomes. We herein report the development of a series of small molecule Stat3 inhibitors with potent anti-MM activity in vitro. These compounds showed high-affinity binding to Stat3's SH2 domain, inhibited intracellular Stat3 phosphorylation, and induced apoptosis in MM cell lines at low micromolar concentrations.
authors: Department of Chemical and Physical Sciences, University of Toronto Mississauga , 3359 Mississauga Road, Mississauga, Ontario, Canada L5L 1C6.
authors: Brent D G
authors: BD
authors: Page
authors: Danielle C
authors: DC
authors: Croucher
authors: Zhi Hua
authors: ZH
authors: Li
authors: Sina
authors: S
authors: Haftchenary
authors: Victor H
authors: VH
authors: Jimenez-Zepeda
authors: Jennifer
authors: J
authors: Atkinson
authors: Paul A
authors: PA
authors: Spagnuolo
authors: Yoong Lim
authors: YL
authors: Wong
authors: Robert
authors: R
authors: Colaguori
authors: Andrew M
authors: AM
authors: Lewis
authors: Aaron D
authors: AD
authors: Schimmer
authors: Suzanne
authors: S
authors: Trudel
authors: Patrick T
authors: PT
authors: Gunning
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018909:src Homology Domains / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human