二氢月桂酸脱氢酶
化学
甲酰胺
嘧啶代谢
白血病
药理学
嘧啶
酶
生物化学
癌症研究
嘌呤
免疫学
医学
作者
Justin S. Cisar,Christine Pietsch,Lindsey G. DeRatt,Edgar Jacoby,Faraz Kazmi,Colleen Keohane,Katie Legenski,Rosalie Matico,Paul Shaffer,Yvan Simonnet,Alexandra Tanner,Chaoyuan Wang,Weixue Wang,Ricardo M. Attar,James P. Edwards,Scott D. Kuduk
标识
DOI:10.1021/acs.jmedchem.2c00788
摘要
Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29, have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.
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