Background/Purpose:

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

pharmacologic properties.

Methods:

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.

Results:

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

(MIF-2).

Conclusion:

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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-pharmacologic-mif-antagonists-by-structure-based-molecular-design/