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Molecules. 2017 Nov 9;22(11). pii: E1936. doi: 10.3390/molecules22111936.

Synthesis and Molecular Modeling Studies of N'-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Lee DH1,2, Lee JY3, Jeong J4, Kim M5,6, Lee KW7,8, Jang E9, Ahn S10,11, Lee CH12,13, Hwang JY14,15,16.

Author information

1
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. ldh1125@krict.re.kr.
2
Department of Chemistry, Sogang University, Seoul 121-742, Korea. ldh1125@krict.re.kr.
3
Korea Chemical Bank, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea. leejy@krict.re.kr.
4
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. chemworld@hanmail.net.
5
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. miok@krict.re.kr.
6
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. miok@krict.re.kr.
7
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. ek00322@krict.re.kr.
8
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. ek00322@krict.re.kr.
9
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. eunseooo@krict.re.kr.
10
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. sahn@krict.re.kr.
11
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Korea. sahn@krict.re.kr.
12
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. lee2014@krict.re.kr.
13
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. lee2014@krict.re.kr.
14
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. jyhwang@krict.re.kr.
15
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. jyhwang@krict.re.kr.
16
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Korea. jyhwang@krict.re.kr.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N'-hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme. Molecular docking studies revealed that 8a binds to IDO1 with the same binding mode as the analog, epacadostat (INCB24360). Here, we report the synthesis and biological evaluation of these hydroxyindazolecarboximidamides and present the molecular docking study of 8a with IDO1.

KEYWORDS:

N’-hydroxyindazolecarboximidamide; cancer immunotherapy; indoleamine 2,3-dioxygenase 1; kynurenine production; tryptophan depletion

PMID:
29120388
PMCID:
PMC6150275
DOI:
10.3390/molecules22111936
[Indexed for MEDLINE]
Free PMC Article

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