O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

William P. Malachowski, Maria Winters, James B. DuHadaway, Ariel Lewis-Ballester, Shorouk Badir, Jenny Wai, Maisha Rahman, Eesha Sheikh, Judith M. LaLonde, Syun-Ru Yeh, George C. Prendergast, Alexander J. Muller

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.

Original languageEnglish (US)
Pages (from-to)564-576
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume108
DOIs
StatePublished - Jan 27 2016

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Derivatives
Halogens
Virus Diseases
Heme
Toxicity
Iron
Ligands
Atoms
Therapeutics
Pharmaceutical Preparations
benzyloxyamine
Neoplasms

Keywords

  • Antitumor therapy
  • IDO1 inhibition
  • O-alkylhydroxylamines
  • Rational drug design

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Malachowski, W. P., Winters, M., DuHadaway, J. B., Lewis-Ballester, A., Badir, S., Wai, J., ... Muller, A. J. (2016). O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1. European Journal of Medicinal Chemistry, 108, 564-576. https://doi.org/10.1016/j.ejmech.2015.12.028

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1. / Malachowski, William P.; Winters, Maria; DuHadaway, James B.; Lewis-Ballester, Ariel; Badir, Shorouk; Wai, Jenny; Rahman, Maisha; Sheikh, Eesha; LaLonde, Judith M.; Yeh, Syun-Ru; Prendergast, George C.; Muller, Alexander J.

In: European Journal of Medicinal Chemistry, Vol. 108, 27.01.2016, p. 564-576.

Research output: Contribution to journalArticle

Malachowski, WP, Winters, M, DuHadaway, JB, Lewis-Ballester, A, Badir, S, Wai, J, Rahman, M, Sheikh, E, LaLonde, JM, Yeh, S-R, Prendergast, GC & Muller, AJ 2016, 'O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1', European Journal of Medicinal Chemistry, vol. 108, pp. 564-576. https://doi.org/10.1016/j.ejmech.2015.12.028
Malachowski, William P. ; Winters, Maria ; DuHadaway, James B. ; Lewis-Ballester, Ariel ; Badir, Shorouk ; Wai, Jenny ; Rahman, Maisha ; Sheikh, Eesha ; LaLonde, Judith M. ; Yeh, Syun-Ru ; Prendergast, George C. ; Muller, Alexander J. / O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 108. pp. 564-576.
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