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本文引用的文献

1
Preclinical Characterization of Linrodostat Mesylate, a Novel, Potent, and Selective Oral Indoleamine 2,3-Dioxygenase 1 Inhibitor.甲磺酸林罗司他的临床前特征：一种新型、强效、选择性的口服吲哚胺 2,3-双加氧酶 1 抑制剂。
Mol Cancer Ther. 2021 Mar;20(3):467-476. doi: 10.1158/1535-7163.MCT-20-0251. Epub 2020 Dec 9.
2
ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer.ENERGIZE：一项新辅助化疗单药或联合纳武利尤单抗加/不加甲磺酸林多司他治疗肌层浸润性膀胱癌的 III 期研究。
Future Oncol. 2020 Jan;16(2):4359-4368. doi: 10.2217/fon-2019-0611. Epub 2019 Dec 11.
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Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1).吲哚胺 2,3-双加氧酶 1（IDO1）的抑制机制。
J Med Chem. 2019 Oct 10;62(19):8784-8795. doi: 10.1021/acs.jmedchem.9b00942. Epub 2019 Sep 26.
4
Discovery of Clinical Candidate (1,4)-4-(()-2-(()-6-Fluoro-5-imidazo[5,1-]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1.发现临床候选药物（1,4）-4-((()-2-((()-6-氟-5-咪唑并[5,1-]异吲哚-5-基)-1-羟基乙基)环己基-1-醇（Navoximod），一种有效的、选择性的吲哚胺 2,3-双加氧酶 1 抑制剂。
J Med Chem. 2019 Jul 25;62(14):6705-6733. doi: 10.1021/acs.jmedchem.9b00662. Epub 2019 Jul 2.
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Echoes of a failure: what lessons can we learn?失败的回响：我们能吸取哪些教训？
Lancet Oncol. 2019 Aug;20(8):1037-1039. doi: 10.1016/S1470-2045(19)30312-2. Epub 2019 Jun 17.
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Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1.绘制自杀抑制剂在人吲哚胺 2,3-双加氧酶 1 中的结合轨迹。
J Am Chem Soc. 2018 Nov 7;140(44):14538-14541. doi: 10.1021/jacs.8b07994. Epub 2018 Oct 24.
7
Updates in the Clinical Development of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for Human Cancers.依帕卡托及其他吲哚胺2,3-双加氧酶1抑制剂（IDO1）用于人类癌症临床开发的进展
Front Oncol. 2018 Oct 4;8:423. doi: 10.3389/fonc.2018.00423. eCollection 2018.
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A Role for Tryptophan-2,3-dioxygenase in CD8 T-cell Suppression and Evidence of Tryptophan Catabolism in Breast Cancer Patient Plasma.色氨酸 2,3-双加氧酶在 CD8 T 细胞抑制中的作用及乳腺癌患者血浆中色氨酸代谢的证据。
Mol Cancer Res. 2019 Jan;17(1):131-139. doi: 10.1158/1541-7786.MCR-18-0362. Epub 2018 Aug 24.
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Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry.吲哚胺2,3-双加氧酶1药物化学的进展。
Medchemcomm. 2017 May 16;8(7):1378-1392. doi: 10.1039/c7md00109f. eCollection 2017 Jul 1.
10
A new cancer immunotherapy suffers a setback.一种新的癌症免疫疗法遭遇挫折。
Science. 2018 May 11;360(6389):588. doi: 10.1126/science.360.6389.588.

吲哚胺-2,3-双加氧酶1强效选择性抑制剂BMS-986242的发现及临床前评估

Discovery and Preclinical Evaluation of BMS-986242, a Potent, Selective Inhibitor of Indoleamine-2,3-dioxygenase 1.

作者信息

Cherney Emily C, Zhang Liping, Nara Susheel, Zhu Xiao, Gullo-Brown Johnni, Maley Derrick, Lin Tai-An, Hunt John T, Huang Christine, Yang Zheng, Darienzo Celia, Discenza Lorell, Ranasinghe Asoka, Grubb Mary, Ziemba Theresa, Traeger Sarah C, Li Xin, Johnston Kathy, Kopcho Lisa, Fereshteh Mark, Foster Kimberly, Stefanski Kevin, Fargnoli Joseph, Swanson Jesse, Brown Jennifer, Delpy Diane, Seitz Steven P, Borzilleri Robert, Vite Gregory, Balog Aaron

机构信息

Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Rd, Lawrence Township, New Jersey 08648, United States.

Biocon BMS R&D Center, Bommasandra Jigani Link Rd, Bommasandra Industrial Area, Bengaluru, Karnataka 560099, India.

出版信息

ACS Med Chem Lett. 2021 Jan 28;12(2):288-294. doi: 10.1021/acsmedchemlett.0c00668. eCollection 2021 Feb 11.

DOI:10.1021/acsmedchemlett.0c00668
PMID:33603977
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7883469/
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both potency and pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development.

摘要

吲哚胺2,3-双加氧酶1（IDO1）是一种与癌症免疫反应相关的含血红素双加氧酶。本报告详细介绍了BMS-986242的发现，这是一种新型IDO1抑制剂，设计用于治疗多种癌症，包括转移性黑色素瘤和肾细胞癌。鉴于癌症免疫治疗对该靶点的浓厚兴趣，我们试图鉴定一种结构上有差异的临床候选药物，其在小鼠异种移植模型中的效力和药效学效应与林罗司他（BMS-986205）相当。基于其临床前特征，BMS-986242被选为临床开发候选药物。