LAUSR

Simple Summary Despite their documented antitumor effects, thienopyrazole-based compounds remain an underexplored class of molecules. In this study, a screening of 2000 novel molecules revealed a unique thienopyrazole derivative, Tpz-1, that elicited potent and selective programmed cell death in human blood, breast, colon, and cervical cancer cell lines when compared to non-cancerous human fibroblast (Hs27) cells. Furthermore, in HL-60 leukemia cells, Tpz-1 interfered with components of signaling pathways and the cytoskeleton that are important to cell shape, internal organization, growth, and division. These findings encourage the continued investigation and development of Tpz-1 and other thienopyrazole derivatives to target and treat cancers. Abstract 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.