Abstract
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.
Keywords:
Acute myeloid leukemia; Brequinar; Dihydroorotate dehydrogenase; Inhibitor.
Copyright © 2020 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dihydroorotate Dehydrogenase
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Mice
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Microsomes, Liver / chemistry
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Microsomes, Liver / metabolism
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Molecular Structure
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Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
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Oxidoreductases Acting on CH-CH Group Donors / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Biphenyl Compounds
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Carboxylic Acids
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Dihydroorotate Dehydrogenase
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Enzyme Inhibitors
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brequinar
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Oxidoreductases Acting on CH-CH Group Donors