Photoaffinity Probe Reveals the Potential Target of Harringtonolide for Cancer Cell Migration Inhibition.

Harringtonolide (HO, 1) is a bioactive diterpenoid tropone isolated from Cephalotaxus harringtonia with antiproliferation activity. Until now there have been no reports to elucidate its anticancer mechanism. Herein we report the synthesis of HO-derived probes (10, 11, and 12) to identify the possible target of HO. As a result, the application of a novel photoaffinity alkyne-tagged probe from HO (compound 12) showed direct engagement between HO and receptor for activated C kinase 1 (RACK1). Furthermore, HO could suppress the epithelial-mesenchymal transition (EMT) process and inhibit activation of the FAK/Src/STAT3 signaling pathway in A375 cells. This study provides a groundwork for HO as an effective antitumor agent that targets RACK1 to suppress cancer cell migration.

Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer.

To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC50 = 18.2 µM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC50 = 1.08 µM). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric binding pocket by forming various interactions in GLS1. The intraperitoneal administration of 7 at a dose of 50 mg/kg exhibited remarkable therapeutic effects and no apparent toxicity in the MDA-MB-231 xenograft model, indicating its potential as a novel GLS1 inhibitor for treatment of TNBC.