2. Academic Validation
  3. Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors

Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors

  • ACS Med Chem Lett. 2018 Mar 26;9(4):312-317. doi: 10.1021/acsmedchemlett.7b00487.
Kun Fang 1 2,  Guoqiang Dong 2,  Yu Li 2,  Shipeng He 1,  Ying Wu 2,  Shanchao Wu 2,  Wei Wang 1 3,  Chunquan Sheng 2
Affiliations

Affiliations

  • 1 School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
  • 2 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China.
  • 3 Department of Chemistry and Chemical Biology, University of New Mexico, MSC03 2060, Albuquerque, New Mexico 87131-0001, United States.
PMID: 29670692 DOI: 10.1021/acsmedchemlett.7b00487
Abstract

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 (IC50 = 69.0 nM) and HDAC1 (IC50 = 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.

Figures
Products