A carboxylic acid isostere screen of the DHODH inhibitor Brequinar

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127589. doi: 10.1016/j.bmcl.2020.127589. Epub 2020 Sep 29.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dihydroorotate Dehydrogenase
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Biphenyl Compounds
  • Carboxylic Acids
  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • brequinar
  • Oxidoreductases Acting on CH-CH Group Donors