1. Discovery of STAT3 and Histone Deacetylase (HDAC) Dual-Pathway Inhibitors for the Treatment of Solid Cancer
- Author
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Chengying Wan, Jiawen Zhu, Shanshan Li, Sihui Long, Dongmei Song, Guiping Cai, Yuhao Ren, Ren Zhu, Wenying Yu, and Ling-Yi Kong
- Subjects
STAT3 Transcription Factor ,Pterostilbene ,Antineoplastic Agents ,Breast Neoplasms ,Hydroxamic Acids ,medicine.disease_cause ,01 natural sciences ,Histone Deacetylases ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Stilbenes ,Drug Discovery ,medicine ,Animals ,Humans ,IC50 ,Vorinostat ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Hydroxamic acid ,Rats ,0104 chemical sciences ,Histone Deacetylase Inhibitors ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,Cancer research ,Molecular Medicine ,Female ,Histone deacetylase ,Drug Screening Assays, Antitumor ,Pharmacophore ,Carcinogenesis ,Half-Life ,medicine.drug - Abstract
Nowadays, simultaneous inhibition of multiple targets through drug combination is an important anticancer strategy owing to the complex mechanism behind tumorigenesis. Recent studies have demonstrated that the inhibition of histone deacetylases (HDACs) will lead to compensated activation of a notorious cancer-related drug target, signal transducer and activator of transcription 3 (STAT3), in breast cancer through a cascade, which probably limits the anti-proliferation effect of HDAC inhibitors in solid tumors. By incorporating the pharmacophore of the HDAC inhibitor SAHA (vorinostat) into the STAT3 inhibitor pterostilbene, a series of potent pterostilbene hydroxamic acid derivatives with dual-target inhibition activity were synthesized. An excellent hydroxamate derivate, compound 14, inhibited STAT3 (KD = 33 nM) and HDAC (IC50 = 23.15 nM) with robust potency in vitro. Compound 14 also showed potent anti-proliferation ability in vivo and in vitro. Our study provides the first STAT3 and HDAC dual-target inhibitor for further exploration.
- Published
- 2021