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ACS Med Chem Lett DOI:10.1021/acsmedchemlett.6b00316

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

Publication TypeJournal Article
Year of Publication2016
AuthorsLewis, TA, Sykes, DB, Law, JM, Munoz, B, Rustiguel, JK, Nonato, MCristina, Scadden, DT, Schreiber, SL
JournalACS Med Chem Lett
Date Published2016 Dec 08

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.


Alternate JournalACS Med Chem Lett
PubMed ID27994748
PubMed Central IDPMC5150668
Grant ListR03 DA032471 / DA / NIDA NIH HHS / United States
U01 CA176152 / CA / NCI NIH HHS / United States
U01 CA217848 / CA / NCI NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States