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

Fingerprint

Thiadiazines
Drug Discovery
Scaffolds
Substitution reactions
Genes
pyrazole

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

Cite this

Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors. / LaPorte, Matthew G.; Wang, Zhuzhu; Colombo, Raffaele; Garzan, Atefeh; Peshkov, Vsevolod A.; Liang, Mary; Johnston, Paul A.; Schurdak, Mark E.; Sen, Malabika; Camarco, Daniel P.; Hua, Yun; Pollock, Netanya I.; Lazo, John S.; Grandis, Jennifer R.; Wipf, Peter; Huryn, Donna M.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 15, 01.01.2016, p. 3581-3585.

Research output: Contribution to journalArticle

LaPorte, MG, Wang, Z, Colombo, R, Garzan, A, Peshkov, VA, Liang, M, Johnston, PA, Schurdak, ME, Sen, M, Camarco, DP, Hua, Y, Pollock, NI, Lazo, JS, Grandis, JR, Wipf, P & Huryn, DM 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, vol. 26, no. 15, pp. 3581-3585. https://doi.org/10.1016/j.bmcl.2016.06.017
LaPorte, Matthew G. ; Wang, Zhuzhu ; Colombo, Raffaele ; Garzan, Atefeh ; Peshkov, Vsevolod A. ; Liang, Mary ; Johnston, Paul A. ; Schurdak, Mark E. ; Sen, Malabika ; Camarco, Daniel P. ; Hua, Yun ; Pollock, Netanya I. ; Lazo, John S. ; Grandis, Jennifer R. ; Wipf, Peter ; Huryn, Donna M. / Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 15. pp. 3581-3585.
@article{664ccc1aeac347698a58a02e75fb5da3,
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.",
keywords = "Anti-cancer agents, STAT1, STAT3 inhibitor, Triazolo-thiadiazines",
author = "LaPorte, {Matthew G.} and Zhuzhu Wang and Raffaele Colombo and Atefeh Garzan and Peshkov, {Vsevolod A.} and Mary Liang and Johnston, {Paul A.} and Schurdak, {Mark E.} and Malabika Sen and Camarco, {Daniel P.} and Yun Hua and Pollock, {Netanya I.} and Lazo, {John S.} and Grandis, {Jennifer R.} and Peter Wipf and Huryn, {Donna M.}",
year = "2016",
month = "1",
day = "1",
doi = "10.1016/j.bmcl.2016.06.017",
language = "English",
volume = "26",
pages = "3581--3585",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier",
number = "15",

}

TY - JOUR

T1 - Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors

AU - LaPorte, Matthew G.

AU - Wang, Zhuzhu

AU - Colombo, Raffaele

AU - Garzan, Atefeh

AU - Peshkov, Vsevolod A.

AU - Liang, Mary

AU - Johnston, Paul A.

AU - Schurdak, Mark E.

AU - Sen, Malabika

AU - Camarco, Daniel P.

AU - Hua, Yun

AU - Pollock, Netanya I.

AU - Lazo, John S.

AU - Grandis, Jennifer R.

AU - Wipf, Peter

AU - Huryn, Donna M.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - Anti-cancer agents

KW - STAT1

KW - STAT3 inhibitor

KW - Triazolo-thiadiazines

UR - http://www.scopus.com/inward/record.url?scp=84978807309&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978807309&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2016.06.017

DO - 10.1016/j.bmcl.2016.06.017

M3 - Article

C2 - 27381083

AN - SCOPUS:84978807309

VL - 26

SP - 3581

EP - 3585

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 15

ER -