A carboxylic acid isostere screen of the DHODH inhibitor Brequinar

[Display omitted] Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) dem...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 30; no. 22; pp. 127589 - 127593
Main Authors DeRatt, Lindsey G., Christine Pietsch, E., Tanner, Alexandra, Shaffer, Paul, Jacoby, Edgar, Wang, Weixue, Kazmi, Faraz, Zhang, Xiaochun, Attar, Ricardo M., Edwards, James P., Kuduk, Scott D.
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 15.11.2020
Elsevier
Subjects
Acute myeloid leukemia
Brequinar
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Dihydroorotate dehydrogenase
Inhibitor
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
Brequinar
Inhibitor
Acute myeloid leukemia
Dihydroorotate dehydrogenase
TRIAL
SODIUM
DESIGN
NSC-368390
MULTICENTER PHASE-II
DIFFERENTIATION
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Summary:[Display omitted] Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127589