title: Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors.
abstract: Structure-activity relationship studies of a 1,2,4-triazolo-[3,4-b]thiadiazine scaffold, identified in an HTS campaign for selective STAT3 pathway inhibitors, determined that a pyrazole group and specific aryl substitution on the thiadiazine were necessary for activity. Improvements in potency and metabolic stability were accomplished by the introduction of an α-methyl group on the thiadiazine. Optimized compounds exhibited anti-proliferative activity, reduction of phosphorylated STAT3 levels and effects on STAT3 target genes. These compounds represent a starting point for further drug discovery efforts targeting the STAT3 pathway.
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: LaPorte
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Zhuzhu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Colombo
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Garzan
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Peshkov
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Johnston
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA; University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schurdak
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Malabika
authors.initials: M
authors.lastname: Sen
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Camarco
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Netanya I
authors.initials: NI
authors.lastname: Pollock
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Lazo
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, CA 94158, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA; University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013829:Thiadiazines; D014230:Triazoles; C031280:pyrazole
keywords: Anti-cancer agents; STAT1; STAT3 inhibitor; Triazolo-thiadiazines