Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)

https://doi.org/10.1016/j.bmcl.2010.07.129Get rights and content

Abstract

The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also exhibits keto–enol tautomerase activity, believed to be vestigial in mammals. Starting from a 1 μM hit from virtual screening, substituted benzoxazol-2-ones have been discovered as antagonists with IC50 values as low as 7.5 nM in a tautomerase assay and 80 nM in a MIF–CD74 binding assay. Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts.

Graphical abstract

Substituted benzoxazol-2-ones are reported as antagonists of the signaling by macrophage migration inhibitory factor (MIF). One of the potent analogues is shown to attenuate MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts.

  1. Download : Download full-size image

Section snippets

Acknowledgments

Gratitude is expressed to T. Lam and E. Voss of the Keck Biotechnology Facility and the National Institutes of Health (AIO42310, AR049610, AR050498, GM032136) for support.

References and notes (24)

  • X. Shi et al.

    Immunity

    (2006)
  • L.R. McLean et al.

    Bioorg. Med. Chem. Lett.

    (2010)
  • R. Bucala

    Nature

    (2000)
  • M. Orita et al.

    Curr. Pharm. Des.

    (2002)
  • E.F. Morand et al.

    Nat. Rev. Drug Disc.

    (2006)
  • L. Leng et al.

    J. Exp. Med.

    (2003)
  • K.L. Meyer-Siegler et al.

    J. Immunol.

    (2006)
  • G. Fingerle-Rowson et al.

    Mol. Cell Biol.

    (2009)
  • P.D. Senter et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • J.B. Lubetsky et al.

    Biochemistry

    (1999)
  • S.L. Stamps et al.

    Biochemistry

    (1998)
  • T.A. Soares et al.

    J. Mol. Recognit.

    (2000)
  • Cited by (66)

    • The N-terminus of MIF regulates the dynamic profile of residues involved in CD74 activation

      2021, Biophysical Journal
      Citation Excerpt :

      Homology modeling with two bacterial proteins led to the identification of its keto-enol tautomerase activity (9). The keto-enol tautomerization site, which is located at the N-terminus of MIF and controlled by the catalytically active residue Pro1 (10), remains the sole target for identification and development of small molecule MIF ligands that serve as modulators of CD74 activity (11–14). Pro1 is buried in the catalytic pocket formed by the assembly of the trimer, and its key position on the extension of β1 strand regulates the flexibility of the MIF β-sheet.

    View all citing articles on Scopus
    View full text