Identification and Characterization of a Novel Dual Inhibitor of Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase

International Journal of Tryptophan Research

article

Saeko Yoshioka¹  Tomonori Ikeda¹  Sogo Fukuchi¹  Yurika Kawai¹  Katsumi Ohta¹  Hisashi Murakami¹  Naohisa Ogo¹  Daisuke Muraoka²  Osamu Takikawa³  Akira Asai¹ 

[1] Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka;Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences;National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology

关键词: Tryptophan;    kynurenine;    indoleamine-pyrrole 2;    3-dioxygenase (IDO1);    tryptophan 2;    3-dioxygenase (TDO);    mitogen-activated protein kinase kinase (MEK);    dual inhibitor;    immunotherapy;    drug screening;   

DOI  :  10.1177/11786469221138456

学科分类：生理学与病理学

来源: Sage Journals

【 摘 要 】

Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first and rate-limiting step of the Kyn pathway. To identify new small molecule inhibitors of TDO, we selected A172 glioblastoma cell line constitutively expressed TDO. Characterization of this cell line using kinase inhibitor library resulted in identification of MEK/ERK pathway-dependent TDO expression. After knowing the properties for TDO expression, we further proceeded to screen chemical library for TDO inhibitors. We previously determined that S-benzylisothiourea derivatives are enzymatic inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and suggested that the isothiourea moiety could be an important pharmacophore for binding to heme. Based on this premise, we screened an in-house library composed of various isothiourea derivatives and identified a bisisothiourea derivative, PVZB3001, as an inhibitor of TDO. Interestingly, PVZB3001 also inhibited the enzymatic activity of IDO1 in both cell-based and cell-free assays but did not inhibit other heme enzymes. Molecular docking studies suggested the importance of isothiourea moieties at the ortho position of the phenyl ring for the inhibition of catalytic activity. PVZB3001 showed competitive inhibition against TDO, and this was supported by the docking simulation. PVZB3001 recovered natural killer (NK) cell viability and functions by inhibiting Kyn accumulation in conditioned medium of both IDO1- and TDO-expressing cells. Furthermore, oral administration of IDO1-overexpressing tumor-bearing mice with PVZB3001 significantly inhibited tumor growth. Thus, we identified a novel selective dual inhibitor of IDO1 and TDO using the Kyn production assay with a glioblastoma cell line. This inhibitor could be a useful pharmacological tool for modulating the Kyn pathway in a variety of experimental systems.

【 授权许可】

CC BY|CC BY-NC