title: Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein.
abstract: We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation eventsin vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, includingMYCandMCL1, and, as a result, leads to apoptosis. We believe13arepresents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Abbarna A
authors.initials: AA
authors.lastname: Cumaraswamy
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Mulu
authors.initials: M
authors.lastname: Geletu
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Todic
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Diego B
authors.initials: DB
authors.lastname: Diaz
authors.affiliation: Department of Physical & Environmental Sciences, University of Toronto at Scarborough , Toronto, Ontario M1C 1A4, Canada.
authors.forename: Xin Ran
authors.initials: XR
authors.lastname: Cheng
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Carla E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Princess Margaret Cancer Centre, Ontario Cancer Institute , 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Rob C
authors.initials: RC
authors.lastname: Laister
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio 45229, United States.
authors.forename: David
authors.initials: D
authors.lastname: Muench
authors.affiliation: Department of Physical & Environmental Sciences, University of Toronto at Scarborough , Toronto, Ontario M1C 1A4, Canada.
authors.forename: Kagan
authors.initials: K
authors.lastname: Kerman
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio 45229, United States.
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
authors.affiliation: Princess Margaret Cancer Centre, Ontario Cancer Institute , 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
keywords: STAT5; anticancer drug; leukemia cells; protein−protein interactions; small-molecule inhibitor