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Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors
- Source :
- ACS Medicinal Chemistry Letters. 9:312-317
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
Abstract
- [Image: see text] In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC(50) = 69.0 nM) and HDAC1 (IC(50) = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.
- Subjects :
- 0301 basic medicine
medicine.medical_treatment
Organic Chemistry
Biochemistry
HDAC1
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Cancer immunotherapy
chemistry
In vivo
030220 oncology & carcinogenesis
Drug Discovery
Cancer cell
medicine
Cancer research
Histone deacetylase
Epigenetics
Indoleamine 2,3-dioxygenase
Lead compound
Subjects
Details
- ISSN :
- 19485875
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- ACS Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....06f1fc84794906a364afdeaeb6f66601
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.7b00487