1. Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors
- Author
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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, and Huryn, Donna M
- Subjects
Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biotechnology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Antineoplastic Agents ,Cell Line ,Tumor ,Cell Proliferation ,Dose-Response Relationship ,Drug ,Drug Screening Assays ,Antitumor ,Humans ,Molecular Structure ,Pyrazoles ,STAT3 Transcription Factor ,Structure-Activity Relationship ,Thiadiazines ,Triazoles ,STAT3 inhibitor ,Triazolo-thiadiazines ,Anti-cancer agents ,STAT1 ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Medicinal and biomolecular chemistry ,Organic chemistry - 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.
- Published
- 2016