异恶唑胺作为色氨酸2,3-双加氧酶2（TDO2）的强效抑制剂
Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2).
作者信息
Pei Zhonghua, Mendonca Rohan, Gazzard Lewis, Pastor Richard, Goon Leanne, Gustafson Amy, VanderPorten Erica, Hatzivassiliou Georgia, Dement Kevin, Cass Robert, Yuen Po-Wai, Zhang Yamin, Wu Guosheng, Lin Xingyu, Liu Yichin, Sellers Benjamin D
机构信息
Department of Discovery Chemistry, Department of Biochemical and Cellular Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Pharmaron-Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
出版信息
ACS Med Chem Lett. 2018 Apr 2;9(5):417-421. doi: 10.1021/acsmedchemlett.7b00427. eCollection 2018 May 10.
Abstract
Tryptophan 2,3-dioxygenase 2 (TDO2) catalyzes the conversion of tryptophan to the immunosuppressive metabolite kynurenine. TDO2 overexpression has been observed in a number of cancers; therefore, TDO inhibition may be a useful therapeutic intervention for cancers. We identified an aminoisoxazole series as potent TDO2 inhibitors from a high-throughput screen (HTS). An extensive medicinal chemistry effort revealed that both the amino group and the isoxazole moiety are important for TDO2 inhibitory activity. Computational modeling yielded a binding hypothesis and provided insight into the observed structure-activity relationships. The optimized compound is a potent TDO2 inhibitor with modest selectivity over indolamine 2,3-dioxygenase 1 (IDO1) and with improved human whole blood stability.
摘要
色氨酸2,3-双加氧酶2（TDO2）催化色氨酸转化为免疫抑制代谢物犬尿氨酸。在许多癌症中都观察到TDO2过表达；因此，抑制TDO可能是一种有效的癌症治疗干预措施。我们通过高通量筛选（HTS）确定了一个氨基异恶唑系列作为有效的TDO2抑制剂。广泛的药物化学研究表明，氨基和异恶唑部分对TDO2抑制活性都很重要。计算模型得出了一个结合假说，并为观察到的构效关系提供了深入了解。优化后的化合物是一种有效的TDO2抑制剂，对吲哚胺2,3-双加氧酶1（IDO1）具有适度的选择性，并且具有改善的人全血稳定性。
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