4.5 Article

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

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

  1. NIH [1R03DA032471-01]
  2. NIH Molecular Library Program [1 U54 HG005032-1]
  3. Bayer
  4. American Society of Hematology
  5. Alex's Lemonade Stand Foundation
  6. Leukemia and Lymphoma Society
  7. Harvard Catalyst
  8. American Cancer Society Institutional Research Grant
  9. Harvard Stem Cell Institute
  10. Amelia Peabody Charitable Fund
  11. Gerald and Darlene Jordan Chair of Medicine at Harvard University
  12. Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/25075-0]

向作者/读者索取更多资源

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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