Evo312: An Evodiamine Analog and Novel PKCβI Inhibitor with Potent Antitumor Activity in Gemcitabine-Resistant Pancreatic Cancer

As an obstinate cancer pancreatic cancer (PC) poses a major challenge due to limited treatment options which include resection surgery, radiation therapy, and gemcitabine-based chemotherapy. In cancer cells, protein kinase C βI (PKCβI) participates in diverse cellular processes, including cell proliferation, invasion, and apoptotic pathways. In the present study, we created a scaffold to develop PKCβI inhibitors using evodiamine-based synthetic molecules. Among the candidate inhibitors, <b>Evo312</b> exhibited the highest antiproliferative efficacy against PC cells, PANC-1, and acquired gemcitabine-resistant PC cells, PANC-GR. Additionally, <b>Evo312</b> robustly inhibited PKCβI activity. Mechanistically, <b>Evo312</b> effectively suppressed the upregulation of PKCβI protein expression, leading to the induction of cell cycle arrest and apoptosis in PANC-GR cells. Furthermore, <b>Evo312</b> exerted an antitumor activity in a PANC-GR cell-implanted xenograft mouse model. These findings position <b>Evo312</b> as a promising lead compound for overcoming gemcitabine resistance in PC through novel mechanisms.