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. 2016 Sep 28;7(12):1112-1117.
doi: 10.1021/acsmedchemlett.6b00316. eCollection 2016 Dec 8.

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

Timothy A Lewis  1 , David B Sykes  2 , Jason M Law  3 , Benito Muñoz  1 , Joane K Rustiguel  4 , Maria Cristina Nonato  4 , David T Scadden  5 , Stuart L Schreiber  6
Affiliations

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

Timothy A Lewis et al. ACS Med Chem Lett. .

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structures of HTS hits 1 and 2.
Scheme 1
Scheme 1. Synthesis of Compound 3 Analogues
Reagents and conditions: (a) EDAC, Et3N/CH2Cl2; (b) TFA/CH2CH2; (c) ArCOCl, Et3N/CH2Cl2.
Figure 2
Figure 2
Crystal structure of DHODH-ML390. 2mFo-DFc electron density for ML390 (carbons in yellow) contoured at 1.0 σ. Dashed in blue are the hydrogen bonds formed between ML390 and Arg136; the red dashes represent the hydrogen bonds between ML390 and Thr360.
See this image and copyright information in PMC

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