2. Academic Validation
  3. Discovery of novel hydroxyamidine derivatives as indoleamine 2,3-dioxygenase 1 inhibitors with in vivo anti-tumor efficacy

Discovery of novel hydroxyamidine derivatives as indoleamine 2,3-dioxygenase 1 inhibitors with in vivo anti-tumor efficacy

  • Bioorg Med Chem Lett. 2020 Apr 15;30(8):127038. doi: 10.1016/j.bmcl.2020.127038.
Chang Liu 1,  Yanyang Nan 2,  Zhifeng Xia 1,  Kedan Gu 1,  Cheng Chen 1,  Xiaochun Dong 1,  Dianwen Ju 3,  Weili Zhao 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
  • 2 Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
  • 3 Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: dianwenju@fudan.edu.cn.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: zhaoweili@fudan.edu.cn.
PMID: 32088128 DOI: 10.1016/j.bmcl.2020.127038
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is closely associated with immune escape in many tumor tissues, and is considered to be a valuable therapeutic target in Cancer Immunotherapy. In this study, the modification of amino sidechain was performed with the hydroxyamidine core kept intact to optimize lead compound Epacadostat. 19 new compounds with hydrazide, thietane or sulfonamide moiety as polar capping group in sidechain were prepared and their IDO1 inhibitory activities were evaluated. Sulfonamide 3a showed potent IDO1 inhibition in both enzymatic and cellular assays with the IC50 value of 71 nM and EC50 value of 11 nM, respectively. Furthermore, in vivo Lewis lung Cancer (LLC) allograft studies of 3a indicated that it handicapped the tumor growth with similar efficacy to Epacadostat. Molecular docking demonstrated that the change of polar capping group affords influence on the orientation of amino ethylene side chain and forms new hydrogen bonding.

Keywords

Cancer immunotherapy; Hydroxyamidine derivatives; Indoleamine 2,3-dioxygenase 1; Lewis lung cancer.

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