Identification of a Unique Cytotoxic Thieno[2,3-c]Pyrazole Derivative with Potent and Selective Anticancer Effects In Vitro
Jessica D. Hess; Luca H. Macias; Denisse A. Gutierrez; Karla Moran-Santibanez; Lisett Contreras; Stephanie Medina; Paulina J. Villanueva; Robert A. Kirken; Armando Varela-Ramirez; Manuel L. Penichet; Renato J. Aguilera
In recent years, the thienopyrazole moiety has emerged as a pharmacologically active scaffold with antitumoral and kinase inhibitory activity. In this study, high-throughput screening of 2000 small molecules obtained from the ChemBridge DIVERset library revealed a unique thieno[2,3-c]pyrazole derivative (Tpz-1) with potent and selective cytotoxic effects on cancer cells. Compound Tpz-1 consistently induced cell death at low micromolar concentrations (0.19 &mu:M to 2.99 &mu:M) against a panel of 17 human cancer cell lines after 24 h, 48 h, or 72 h of exposure. Furthermore, an in vitro investigation of Tpz-1&rsquo:s mechanism of action revealed that Tpz-1 interfered with cell cycle progression, reduced phosphorylation of p38, CREB, Akt, and STAT3 kinases, induced hyperphosphorylation of Fgr, Hck, and ERK 1/2 kinases, and disrupted microtubules and mitotic spindle formation. These findings support the continued exploration of Tpz-1 and other thieno[2,3-c]pyrazole-based compounds as potential small-molecule anticancer agents.
Show more [+] Less [-]AGROVOC Keywords
Bibliographic information
This bibliographic record has been provided by Multidisciplinary Digital Publishing Institute
