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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3581-3585
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number15
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    LaPorte, M. G., Wang, Z., Colombo, R., Garzan, A., Peshkov, V. A., Liang, M., Johnston, P. A., Schurdak, M. E., Sen, M., Camarco, D. P., Hua, Y., Pollock, N. I., Lazo, J. S., Grandis, J. R., Wipf, P., & Huryn, D. M. (2016). Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors. Bioorganic and Medicinal Chemistry Letters, 26(15), 3581-3585. https://doi.org/10.1016/j.bmcl.2016.06.017