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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 ?-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.

SUBMITTER: LaPorte MG

PROVIDER: S-EPMC4964800 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

LaPorte Matthew G MG Wang Zhuzhu Z Colombo Raffaele R Garzan Atefeh A Peshkov Vsevolod A VA Liang Mary M Johnston Paul A PA Schurdak Mark E ME Sen Malabika M Camarco Daniel P DP Hua Yun Y Pollock Netanya I NI Lazo John S JS Grandis Jennifer R JR Wipf Peter P Huryn Donna M DM

Bioorganic & medicinal chemistry letters 20160609 15

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 an ...[more]

PMID: 27381083

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