Identification, Structure–Activity Relationships of Marine-Derived Indolocarbazoles, and a Dual PKCθ/δ Inhibitor with Potent Antipancreatic Cancer Efficacy

作者：Jinhui Wang, Weiyang Jin, Xiaoxin Zhou, Jiaqi Li, Cheng-Dong Xu, Zhongjun Ma, Jianan Wang, Le-Le Qin, Biao Zhou, Wanjing Ding, Tingting Gao, Hangping Yao, Zhe Chen · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.0c01271 · 被引用次数：31 · 研究领域：Microbial Natural Products and Biosynthesis、Cancer Mechanisms and Therapy、Microbial Metabolism and Applications

Abstract Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure–activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15 was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.