Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia

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• 作者：Timothy A. Lewis ; David B. Sykes ; Jason M. Law ; Benito Muñoz ; Joane K. Rustiguel ; Maria Cristina Nonato ; David T. Scadden ; Stuart L. Schreiber
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1112-1117
• 全文大小：315K
• ISSN：1948-5875

文摘

Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.