Targeting the STAT3 pathway with STAT3 degraders.

Signal transducer and activator of transcription 3 (STAT3) has been widely considered as a therapeutic target for various diseases, especially tumors. Thus far, several STAT3 inhibitors have been advanced to clinical trials; however, the development of STAT3 inhibitors is hindered by numerous dilemmas. Fortunately, STAT3 degraders represent an alternative and promising strategy to block STAT3, attracting extensive research interest. Here, we analyze the recent advancements of STAT3 degraders, including proteolysis targeting chimeras (PROTACs) and small-molecule natural products, focusing on their structures, mechanisms, and biological activities. We discuss the potential opportunities and challenges for developing STAT3 degraders. It is hoped that this Review will provide insights into the discovery of potent STAT3-targeting drugs.

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway.

Targeting the programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has evolved into one of the most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved for treating a variety of tumors, while the development of small-molecule PD-1/PD-L1 inhibitors has lagged far behind, with only a few small-molecule inhibitors entering clinical trials. In addition to antibody drugs and small-molecule inhibitors, reducing the expression levels of PD-L1 has attracted extensive research interest as another promising strategy to target the PD-1/PD-L1 pathway. Herein, we analyze the structures and mechanisms of molecules that reduce PD-L1 expression and classify them as degraders and downregulators according to whether they directly bind to PD-L1. Moreover, we discuss the potential prospects for developing PD-L1-targeting drugs based on these molecules. It is hoped that this perspective will provide profound insights into the discovery of potent antitumor immunity drugs.

Three new cardenolides from the fruits of Cascabela thevetia (L.) Lippold and their cytotoxic activities.

Phytochemical investigations on the fruits of Cascabela thevetia (L.) Lippold led to obtain three new cardenolides (1-3) and five known analogues (4-7). Their structures were elucidated by means of UV, IR, HR-ESI-MS, 1D and 2D NMR spectroscopic data analysis. Compounds 1 and 2 represent the first examples of naturally occurring cardenolides with 19-nor-5(10)-ene group and α-l-3-demethyl-thevetose, respectively. Compound 3 is a rare C-nor-D-homocardenolide in nature. All isolated cardenolides (1-7) were evaluated for their cytotoxic activities against four human cancer cell lines (MCF-7, HCT-116, HeLa and HepG2), and the results indicated the compounds with sugar units (1, 2, 4, and 5) exhibited stronger cytotoxic activities with IC50 values ranging between 0.022 and 0.308 µM.