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
  • 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.

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