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

Chang Liu; Yanyang Nan; Zhifeng Xia; Kedan Gu; Cheng Chen; Xiaochun Dong; Dianwen Ju; Weili Zhao

doi:10.1016/j.bmcl.2020.127038

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. Epub 2020 Feb 15.

Authors

Chang Liu¹, Yanyang Nan², Zhifeng Xia¹, Kedan Gu¹, Cheng Chen¹, Xiaochun Dong¹, Dianwen Ju³, Weili Zhao⁴

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidines / chemical synthesis
Amidines / chemistry
Amidines / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HeLa Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Structure-Activity Relationship

Substances

Amidines
Antineoplastic Agents
Enzyme Inhibitors
IDO1 protein, human
Indoleamine-Pyrrole 2,3,-Dioxygenase