Session Title: Cytokines, Mediators, and Gene Regulation
Session Type: Abstract Submissions (ACR)
Cytokine inhibition is becoming a mainstay for the therapy of autoimmunity but
current antibody-based approaches remain limited by high cost, parenteral administration, and
anti-idiotype responses. Orally available, small molecules offer considerable advantages, yet the
discovery of molecules that effectively disrupt the molecular interactions between cytokines and
their receptors remains to be achieved.
Macrophage migration inhibitory factor (MIF) is an attractive drug target because of its genetic
association with autoimmunity and its role in counter-regulating glucocorticoid
immunosuppression. The discovery of the MIF receptor (CD74) together with X-ray
crystallography of MIF has enabled structure-based design using ligand docking, moleculegrowing
computational methodologies, and receptor binding assessment. By this approach, we
are pursuing the discovery of potent and selective MIF antagonists with auspicious
Utilizing a high resolution MIF crystal structure, virtual screening was performed by
docking 2.1 million compounds into the MIF tautomerization site, which was judged to interface
with the MIF receptor. Validation by in vitro functional analyses revealed novel compounds with
μM inhibitory activity in several molecular series. Structure optimization was pursued by
synthesis of substituted benzoxazol-2-ones and MIF receptor binding, MIF ligand selectivity,
and MIF-dependent signal transduction evaluated in vitro.
Binding analysis of MIF interaction with the MIF receptor ectodomain revealed 11
novel compounds with IC50s in the μM range. Beginning with a 1 μM candidate, substituted
benzoxazol-2-ones were discovered with IC50 values as low as 80 nM for MIF receptor
antagonism. One such molecule: 3-(3-hydroxybenzyl)-5-methylbenzo[d]oxazol-2(3H)-one
(Debio 1036) was evaluated more closely and functional inhibition established in synovial
fibroblasts for MIF-dependent ERK1/2 phosphorylation (IC50=5 nM) and invasive phenotype.
Debio 1036 also was 1000-fold more selective for MIF than for its close structural homolog, DDT
Several highly potent, small molecule MIF receptor antagonists have been
identified by a combination of structure-based molecular design and functional analysis.
Compounds with oral bioavailability and auspicious pharmacologic properties are anticipated to
provide promising candidates for the treatment of human autoimmunity.
W. L. Jorgensen,
A. A. Hare,
R. J. Bucala,
« Back to 2012 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-pharmacologic-mif-antagonists-by-structure-based-molecular-design/