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

  • J Med Chem. 2020 Nov 12;63(21):12978-12991. doi: 10.1021/acs.jmedchem.0c01271.
Jinhui Wang  1 ,  Weiyang Jin  2 ,  Xiaoxin Zhou  2 ,  Jiaqi Li  1 ,  Chengdong Xu  1 ,  Zhongjun Ma  1 ,  Jianan Wang  1 ,  Lele Qin  1 ,  Biao Zhou  1 ,  Wanjing Ding  1 ,  Tingting Gao  1 ,  Hangping Yao  3 ,  Zhe Chen  4
Affiliations
  • 1. Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, No. 1 Zheda Road, Zhoushan 316021, China.
  • 2. College of Life and Environmental Sciences, Hangzhou Normal University, No. 2318, Yuhangtang Road, Hangzhou 311121, China.
  • 3. The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, China.
  • 4. Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, No. 548, Binwen Road, Hangzhou 310053, China.
PMID: 33100009 DOI: 10.1021/acs.jmedchem.0c01271
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.