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

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.