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Discovery of novel hydroxyamidine derivatives as indoleamine 2,3-dioxygenase 1 inhibitors with in vivo anti-tumor efficacy.发现新型羟脒衍生物作为吲哚胺 2,3-双加氧酶 1 抑制剂具有体内抗肿瘤功效。
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2
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发现羟基脒衍生物作为高效、选择性吲哚胺-2,3-双加氧酶1抑制剂

Discovery of Hydroxyamidine Derivatives as Highly Potent, Selective Indoleamine-2,3-dioxygenase 1 Inhibitors.

作者信息

Jin Fangfang, Hu Qiyue, Fei Hongbo, Lv Hejun, Wang Shenglan, Gui Bin, Zhang Junzhen, Tu Wangyang, Zhang Yun, Zhang Lei, Wan Hong, Zhang Limin, Hu Bin, Yang Fanglong, Bai Chang, He Feng, Zhang Lianshan, Tao Weikang

机构信息

Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.

Chengdu Suncadia Medicine Co., Ltd., 88 South Keyuan Road, Chengdu, Sichuan 610000, China.

出版信息

ACS Med Chem Lett. 2021 Jan 20;12(2):195-201. doi: 10.1021/acsmedchemlett.0c00443. eCollection 2021 Feb 11.

DOI:10.1021/acsmedchemlett.0c00443
PMID:33603965
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7883375/
Abstract

In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds - and exhibited favorable enzymatic and cellular activities. Compound showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable pharmacokinetic properties, compound was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound as a potential cancer immunotherapy agent should warrant further investigation.

摘要

在本研究中，通过基于结构的药物设计，一系列新型羟基脒衍生物被鉴定为强效且选择性的吲哚胺2,3-双加氧酶1（IDO1）抑制剂。其中，化合物-和表现出良好的酶活性和细胞活性。化合物在小鼠、大鼠和犬中显示出改善的生物利用度（分别为F% = 44%、58.8%、102.1%）。具有合理的药代动力学性质，化合物在转基因MC38异种移植小鼠模型中进一步评估。化合物与PD-1单克隆抗体的联合显示出协同抗肿瘤作用。这些数据表明，化合物作为一种潜在的癌症免疫治疗药物值得进一步研究。