期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 7, 期 12, 页码 1112-1117出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00316
关键词
AML; DHODH; HoxA9; ML390
资金
- NIH [1R03DA032471-01]
- NIH Molecular Library Program [1 U54 HG005032-1]
- Bayer
- American Society of Hematology
- Alex's Lemonade Stand Foundation
- Leukemia and Lymphoma Society
- Harvard Catalyst
- American Cancer Society Institutional Research Grant
- Harvard Stem Cell Institute
- Amelia Peabody Charitable Fund
- Gerald and Darlene Jordan Chair of Medicine at Harvard University
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/25075-0]
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.
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