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Bioorg Med Chem Lett. 2016 Aug 1;26(15):3581-5. doi: 10.1016/j.bmcl.2016.06.017. Epub 2016 Jun 9.

Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors.

Author information

1
University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
2
University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
3
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
4
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA; University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5
Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
6
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
7
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
8
Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, CA 94158, USA.
9
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.

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.

KEYWORDS:

Anti-cancer agents; STAT1; STAT3 inhibitor; Triazolo-thiadiazines

PMID:
27381083
PMCID:
PMC4964800
DOI:
10.1016/j.bmcl.2016.06.017
[Indexed for MEDLINE]
Free PMC Article

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