Selective ALDH3A1 inhibition by benzimidazole analogues increase mafosfamide sensitivity in cancer cells

Bibek Parajuli, Melissa Fishel, Thomas Hurley

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Aldehyde dehydrogenase enzymes irreversibly oxidize aldehydes generated from metabolism of amino acids, fatty acids, food, smoke, additives, and xenobiotic drugs. Cyclophosphamide is one such xenobiotic used in cancer therapies. Upon activation, cyclophosphamide forms an intermediate, aldophosphamide, which can be detoxified to carboxyphosphamide by aldehyde dehydrogenases (ALDH), especially ALDH1A1 and ALDH3A1. Consequently, selective inhibition of ALDH3A1 could increase chemosensitivity toward cyclophosphamide in ALDH3A1 expressing tumors. Here, we report detailed kinetics and structural characterization of a highly selective submicromolar inhibitor of ALDH3A1, 1-[(4-fluorophenyl)sulfonyl]-2-methyl-1H-benzimidazole (CB7, IC50 of 0.2 μM). CB7 does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 activity. Structural, kinetics, and mutagenesis studies show that CB7 binds to the aldehyde binding pocket of ALDH3A1. ALDH3A1-expressing lung adenocarcinoma and glioblastoma cell lines are sensitized toward mafosfamide (MF) treatment in the presence analogues of CB7, whereas primary lung fibroblasts lacking ALDH3A1 expression, are not.

Original languageEnglish
Pages (from-to)449-461
Number of pages13
JournalJournal of Medicinal Chemistry
Volume57
Issue number2
DOIs
StatePublished - Jan 23 2014

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Cyclophosphamide
Aldehyde Dehydrogenase
Xenobiotics
Aldehydes
Neoplasms
Food Additives
Glioblastoma
Smoke
Mutagenesis
Inhibitory Concentration 50
Fatty Acids
Fibroblasts
Amino Acids
Cell Line
Lung
Enzymes
Pharmaceutical Preparations
mafosfamide
benzimidazole
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Selective ALDH3A1 inhibition by benzimidazole analogues increase mafosfamide sensitivity in cancer cells. / Parajuli, Bibek; Fishel, Melissa; Hurley, Thomas.

In: Journal of Medicinal Chemistry, Vol. 57, No. 2, 23.01.2014, p. 449-461.

Research output: Contribution to journalArticle

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