Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia
Year: 2016
Type: article
Abstract: 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.
Source: ACS Medicinal Chemistry Letters
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Cancer Society, Amelia Peabody Charitable Fund, American Society of Hematology, Alex's Lemonade Stand Foundation for Childhood Cancer, Bayer, Leukemia and Lymphoma Society, Massachusetts General Hospital, Harvard University, Harvard Catalyst, European Hematology Association, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Institutes of Health, Harvard Stem Cell Institute, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute
Awards: Broad Institute Comprehensive Screening Center, G1660613235, Development of leishmanicidal drugs based on the selective inhibition of the enzyme dihydroorotate dehydrogenase, Targeting vulnerabilities of therapy-resistant cancer cell states with small molecules, Cancer dependencies associated with genomic alterations and targeted by small mol, Discovering small molecules that overcome differentiation arrest in acute myeloid
OpenAlex ID: W2526797893