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ID: ALA4665887

Journal: J Med Chem

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

Authors: Wang J,Jin W,Zhou X,Li J,Xu C,Ma Z,Wang J,Qin L,Zhou B,Ding W,Gao T,Yao H,Chen Z

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.

CiteXplore: 33100009

DOI: 10.1021/acs.jmedchem.0c01271