A 286982

A 286982 is a selective inhibitor of LFA-1/ICAM-1 binding and LFA-1 with IC50 value of 44 nM and 35 nM, respectively [1].

Lymphocyte function-associated antigen-1 (LFA-1) is a member of leukocyte intergrins family and involves in T cells binding to antigen presenting cells. Intracellular adhension molecule-1 (ICAM-1) is a type of intercellular adhesion molecule and plays a pivotal role in cell-cell interactions. LFA-1/ICAM-1 interaction plays an important role in the pathogenesis of inflammatory disease [2].

A 286982 is a potent LFA-1/ICAM-1 inhibitor and has a different effect on the binding of compound 2B. When tested with LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assays, A-286982 treatment for 28h exhibited inhibition on LFA-1/ICAM-1interaction [1]. Using the LFA-1/ICAM-1 ELISA assay, it was shown that A 286982 exhibited inhibition on the binding of ICAM-1-Ig to LFA-1 by reducing both ligands affinity and binding capacity [3].

References:
[1].  Liu, G., et al., Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead. J Med Chem, 2000. 43(21): p. 4025-40.
[2].  Katakai, T., K. Habiro, and T. Kinashi, Dendritic cells regulate high-speed interstitial T cell migration in the lymph node via LFA-1/ICAM-1. J Immunol, 2013. 191(3): p. 1188-99.
[3].  Keating, S.M., et al., Competition between intercellular adhesion molecule-1 and a small-molecule antagonist for a common binding site on the alphal subunit of lymphocyte function-associated antigen-1. Protein Sci, 2006. 15(2): p. 290-303.

Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead.[Pubmed:11052808]

J Med Chem. 2000 Oct 19;43(21):4025-40.

The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of the beta(2)-integrin family of adhesion molecules, and intracellular adhesion molecule ICAM-1 (cd54) is thought to play a critical role in the inflammatory process. On the basis of an anilino diaryl sulfide screening lead 1, in combination with pharmacophore analysis of other screening hits, we have identified an adjacent binding pocket. Subsequently, a p-ethenylcarbonyl linker was discovered to be optimal for accessing this binding site. Solution-phase parallel synthesis enabled rapid optimization of the cinnamides for this pocket. In conjunction with fine-tuning of the diaryl substituents, we discovered a novel series of potent, nonpeptide inhibitors of LFA-1/ICAM-1 interaction, exemplified by A-286982 (28h), which has IC(50) values of 44 and 35 nM in an LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assay, respectively.

Competition between intercellular adhesion molecule-1 and a small-molecule antagonist for a common binding site on the alphal subunit of lymphocyte function-associated antigen-1.[Pubmed:16384997]

Protein Sci. 2006 Feb;15(2):290-303.

The lymphocyte function-associated antigen-1 (LFA-1) binding of a unique class of small-molecule antagonists as represented by compound 3 was analyzed in comparison to that of soluble intercellular adhesion molecule-1 (sICAM-1) and A-286982, which respectively define direct and allosteric competitive binding sites within LFA-1's inserted (I) domain. All three molecules antagonized LFA-1 binding to ICAM-1-Immunoglobulin G fusion (ICAM-1-Ig) in a competition ELISA, but only compound 3 and sICAM-1 inhibited the binding of a fluorescein-labeled analog of compound 3 to LFA-1. Compound 3 and sICAM-1 displayed classical direct competitive binding behavior with ICAM-1. Their antagonism of LFA-1 was surmountable by both ICAM-1-Ig and a fluorescein-labeled compound 3 analog. The competition of both sICAM-1 and compound 3 with ICAM-1-Ig for LFA-1 resulted in equivalent and linear Schild plots with slopes of 1.24 and 1.26, respectively. Cross-linking studies with a photoactivated analog of compound 3 localized the high-affinity small-molecule binding site to the N-terminal 507 amino acid segment of the alpha chain of LFA-1, a region that includes the I domain. In addition, cells transfected with a variant of LFA-1 lacking this I domain showed no significant binding of a fluorescein-labeled analog of compound 3 or ICAM-1-Ig. These results demonstrate that compound 3 inhibits the LFA-1/ICAM-1 binding interaction in a directly competitive manner by binding to a high-affinity site on LFA-1. This binding site overlaps with the ICAM-1 binding site on the alpha subunit of LFA-1, which has previously been localized to the I domain.