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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Lewis, Timothy A. ; Sykes, David B. ; Law, Jason M. ; Munoz, Benito ; Rustiguel, Joane K. ; Nonato, Maria Cristina ; Scadden, David T. ; Schreiber, Stuart L.
Total Authors: 8
Document type: Journal article
Source: ACS Medicinal Chemistry Letters; v. 7, n. 12, p. 1112-1117, DEC 2016.
Web of Science Citations: 14
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. (AU)

FAPESP's process: 12/25075-0 - Development of leishmanicidal drugs based on the selective inhibition of the enzyme dihydroorotate dehydrogenase
Grantee:Maria Cristina Nonato
Support Opportunities: Regular Research Grants