Marine natural products (MNPs) are considered as great resources for discovery of bioactive lead compounds and development of drug candidates.^1,2 Our group has long been working on discovery of bioactive marine natural products. In the pursuit of novel STAT3 inhibitors, we screened our in-house library via a Janus kinase (JAK)/STAT3 signaling gene reporter assay developed by previously. Among the active compounds, a diketopiperazine OUC1010 isolated from the organic crude extraction of the marine-derived fungus Penicillium janthinellum stood out. It displayed low micromolar cytotoxicity against several cancer cell lines including A549. Its target protein was identified as STAT3 via western blot and surface plasmon resonance (SPR). Computational docking studies of OUC1010 with STAT3 (PDB code: 6NJS) using Schrödinger Small-Molecule Drug Discovery Suite were conducted to illustrate their interactions in detail. It was demonstrated that OUC1010 could well occupy the SH2 binding pocket of STAT3 and form multiple hydrogen bonds with Ser613, Glu549, Glu638 and Ser636. Further structural optimizations and in vivo anti-cancer efficacy studies are undergoing.



Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 41830535; 4217060347; 81874300; 81991525), Key R&D Program of Shandong Province (2020CXGC010503), Shandong Provincial Major Science and Technology Innovation Project (2018SDKJ0402) and the Taishan Scholars Program, China.



References:

1. Carroll, A. R.; Copp, B. R.; Davis, R. A.; Keyzers, R. A.; Prinsep, M. R., Marine natural products. Nat. Prod. Rep. 2019, 36 (1), 122-173.


2. Jimenez, C., Marine Natural Products in Medicinal Chemistry. ACS Med. Chem. Lett. 2018, 9 (10), 959-961.