Discovery of tofacitinib derivatives as orally active antitumor agents based on the scaffold hybridization strategy.

In this work, a novel series of tofacitinib analogs were designed and synthesized based on the scaffold hybridization strategy and then evaluated for their antiproliferative activity toward three gastric cancer cell lines, leading to the identification of compound C18 which exhibited potent inhibitory activity against MGC-803 cell lines with an IC 50 value of 2.68 μM. Compound C18 could effectively inhibit the colony formation, suppress the cell migration and induce apoptosis of MGC-803 cells through activating the p38 and JNK signaling pathways, while C18 showed no obvious effect on the cell cycle distribution in MGC-803 cells. In addition, C18 could initiate mitochondrial dysfunction of MGC-803 cells. Besides, in vivo antitumor studies indicated that C18 could inhibit gastric cancer tumor growth in vivo without obvious global toxicity. Image 1 • New tofacitinib analogs were designed based on the scaffold hybridization strategy. • C18 effectively inhibits colony formation and cell migration of MGC-803 cells. • C18 induces apoptosis of MGC-803 cells through activation of the p38 and JNK signaling pathways. • C18 induces mitochondrial dysfunction of MGC-803 cells. • C18 effectively inhibits tumor growth of xenograft model bearing MGC-803 cells. [ABSTRACT FROM AUTHOR]