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

Autor(es)

Lewis, Timothy A. ; Sykes, David B. ; Law, Jason M. ; Munoz, Benito ; Rustiguel, Joane K. ; Nonato, Maria Cristina ; Scadden, David T. ; Schreiber, Stuart L.

• Tipo de documento: Artigo Científico
• Fonte: ACS Medicinal Chemistry Letters; v. 7, n. 12, p. 1112-1117, DEC 2016.
• Citações Web of Science: 14

Resumo

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. (AU)

• Processo FAPESP: 12/25075-0 - Desenvolvimento de moléculas com ação leishmanicida baseado na inibição seletiva da enzima diidroorotato desidrogenase
• Beneficiário: Maria Cristina Nonato
• Modalidade de apoio: Auxílio à Pesquisa - Regular