作为一种顽固性癌症，胰腺癌（PC）由于治疗选择有限（包括切除手术、放射治疗和基于吉西他滨的化疗）而构成了重大挑战。在癌细胞中，蛋白激酶 C βI (PKCβI) 参与多种细胞过程，包括细胞增殖、侵袭和凋亡途径。在本研究中，我们使用基于吴茱萸碱的合成分子创建了一个支架来开发 PKCβI 抑制剂。在候选抑制剂中，Evo312 对 PC 细胞 PANC-1 和获得性吉西他滨耐药 PC 细胞 PANC-GR 表现出最高的抗增殖功效。此外，Evo312 强烈抑制 PKCβI 活性。从机制上讲，Evo312 有效抑制 PKCβI 蛋白表达的上调，导致 PANC-GR 细胞细胞周期停滞和凋亡。此外，Evo312 在 PANC-GR 细胞植入的异种移植小鼠模型中发挥抗肿瘤活性。这些发现使 Evo312 成为一种有前途的先导化合物，可通过新机制克服 PC 中的吉西他滨耐药性。

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.