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ACS Med Chem Lett. 2016 Sep 28;7(12):1112-1117. eCollection 2016 Dec 8.

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

Author information

1
Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
2
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, United States.
3
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
4
School of Pharmaceutical Sciences, University of São Paulo , Ribeirão Preto, São Paulo 14040-903, Brazil.
5
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, United States; Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, United States.
6
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States; Howard Hughes Medical Institute, Cambridge, Massachusetts 02138, United States.

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.

KEYWORDS:

AML; DHODH; HoxA9; ML390

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