Optimization of pyrazole-containing 1, 2, 4-triazolo-[3, 4-b]thiadiazines, a new class of STAT3 pathway inhibitors. Issue 15 (1st August 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 15(2016)
• Page Start: 3581
• Page End: 3585
• Publication Date: 2016-08-01
• Subjects: STAT3 inhibitor -- Triazolo-thiadiazines -- Anti-cancer agents -- STAT1; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.06.017
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.