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.
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.
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。
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