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Discovery of STAT3 and Histone Deacetylase (HDAC) Dual-Pathway Inhibitors for the Treatment of Solid Cancer
- Source :
- Journal of Medicinal Chemistry. 64:7468-7482
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
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.
- 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
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....8efdecac1c11056187bbfda383d568ad