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, Evo312 exhibited the highest antiproliferative
efficacy against PC cells, PANC-1, and acquired gemcitabine-resistant
PC cells, PANC-GR. Additionally, Evo312 robustly inhibited
PKCβI activity. Mechanistically, Evo312 effectively
suppressed the upregulation of PKCβI protein expression, leading
to the induction of cell cycle arrest and apoptosis in PANC-GR cells.
Furthermore, Evo312 exerted an antitumor activity in
a PANC-GR cell-implanted xenograft mouse model. These findings position Evo312 as a promising lead compound for overcoming gemcitabine
resistance in PC through novel mechanisms.