Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF).
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 IC(50) 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.
Hare
Alissa A
AA
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
Leng
Lin
L
Gandavadi
Sunilkumar
S
Du
Xin
X
Cournia
Zoe
Z
Bucala
Richard
R
Jorgensen
William L
WL
D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D005347:Fibroblasts / Q000201:enzymology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D001583:Benzoxazoles; D000949:Histocompatibility Antigens Class II; D011971:Receptors, Immunologic; C045084:invariant chain; C033184:macrophage migration inhibitory factor receptor; C017057:benzoxazolone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3