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
Affiliations
Jessica D. Hess
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Luca H. Macias
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Denisse A. Gutierrez
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Karla Moran-Santibanez
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Lisett Contreras
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Stephanie Medina
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Paulina J. Villanueva
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Robert A. Kirken
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Armando Varela-Ramirez
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
Manuel L. Penichet
Division of Surgical Oncology, Department of Surgery and Department of Microbiology, Immunology and Molecular Genetics, The Molecular Biology Institute, AIDS Institute, Jonsson Comprehensive Cancer Center, The University of California, Los Angeles, CA 90095, USA
Renato J. Aguilera
Department of Biological Sciences and Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, The University of Texas at El Paso (UTEP), El Paso, TX 79902, USA
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 μM to 2.99 μM) 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’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.
