Triptolide reduces PD-L1 through the EGFR and IFN-γ/IRF1 dual signaling pathways.

As the principal ligand of programmed death 1 (PD-1), PD-L1 can induce the exhaustion of effector T cells and the escape of cancer cells through interacting with PD-1 in many solid malignancies. Therefore, targeting the PD-1/PD-L1 axis has become an attractive strategy in cancer immunotherapy. However, at present, no small-molecule agents targeting PD1/PD-L1 pathways have been successfully used in clinical applications. Here, we first found that the natural product Triptolide could significantly reduce the PD-L1 expression on the surface of NSCLC cells. This down-regulation is related to the activity of EGFR signaling pathway. Moreover, the reduction of PD-L1 caused by Triptolide could be substantially rescued by IFN-γ. Furthermore, our findings suggest that Triptolide significantly inhibits the activity of the IFN-γ-JAK-STAT-IRF1 signaling axis, as evidenced by the noticeable reduction in both basal and phosphorylated levels of STAT3. Thus, in NSCLC cells, Triptolide reduces PD-L1 expression both through the EGFR and IFN-γ/JAK1/JAK2/STAT1/STAT3/IRF1 signaling pathways. The results provide new insights into the application of Triptolide in the immune checkpoints treatment of NSCLCs.

Hydrophobic Tag Tethering Degradation, The Emerging Targeted Protein Degradation Strategy.

Targeted protein degradation (TPD) strategies have become a new trend in drug discovery due to the capability of triggering the degradation of protein of interest (POI) selectively and effectively in recent decades. Particularly, the hydrophobic tag tethering degrader (HyTTD) has drawn a lot of attention and may offer a promising strategy for new drug research and development in the future. Herein, we will give an overview of the development of HyTTD, the structure-activity relationship (SAR) between HyTTD and linkers, HyTs, and ligand motifs, as well as the various HyTTDs targeting different targets, thus offering a rational strategy for the design of HyTTDs in further TPD drug discovery.

Identification of Ziyuglycoside II from a Natural Products Library as a STING Agonist.

Given the emerging pivotal roles of stimulator of interferon genes (STING) in host pathogen defense and immune-oncology, STING is regarded as a promising target for drug development. Cyclic dinucleotides (CDNs) are the first-generation STING agonists. However, their poor metabolic stability and membrane permeability limits their therapeutic application. In contrast, small-molecule STING agonists show superior properties such as molecular weight, polar character, and delivery diversity. The quest for a potent small-molecular agonist of human STING remains ongoing. In our study, through an IRF/IFN pathway-targeted cell-based screen of a natural products library, we identified a small-molecular STING agonist, Ziyuglycoside II, termed ST12, with potent stimulation of the IRF/IFN and NF-κB pathways. Furthermore, its binding to the C-terminal domain of human STING, detected by bio-layer interferometry, indicates that ST12 is a human STING agonist. Further Tanimoto similarity analysis with existing small-molecule STING agonists indicates that ST12 is a lead compound with a novel core structure for the further optimization.