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

Matthew G LaPorte; Zhuzhu Wang; Raffaele Colombo; Atefeh Garzan; Vsevolod A Peshkov; Mary Liang; Paul A Johnston; Mark E Schurdak; Malabika Sen; Daniel P Camarco; Yun Hua; Netanya I Pollock; John S Lazo; Jennifer R Grandis; Peter Wipf; Donna M Huryn

doi:10.1016/j.bmcl.2016.06.017

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Pyrazoles / chemistry
Pyrazoles / pharmacology*
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / metabolism
Structure-Activity Relationship
Thiadiazines / chemical synthesis
Thiadiazines / chemistry
Thiadiazines / pharmacology*
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Antineoplastic Agents
Pyrazoles
STAT3 Transcription Factor
STAT3 protein, human
Thiadiazines
Triazoles
pyrazole

Abstract

Publication types

MeSH terms

Substances

Grants and funding