Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain 1 1Edited by F. E. Cohen

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

“…[19][20][21] Considering the importance of CAM-DR in hematologic and solid neoplasms, 16,17 our current study suggests for the first time that LFA703 and its derivatives may be promising compounds in cancer therapy. Although LFA703 is a statin derivative, which completely lacks HMG-CoA reductase inhibition activity, 18 and although statins such as lovastatin have been shown to inhibit integrin interaction, 22 reversal of CAM-DR by LFA703 was not complete and the role of HMG-CoA reductase still had to be evaluated.…”

Integrins as therapeutic targets: lessons and opportunities

“…has been co-crystalized with a number of small molecule inhibitors 131,[140][141][142][143][144][145] identifying the first model of true allosteric inhibition of an α-I domain (FIG. 5b).…”

“…Crystallographic studies have demonstrated that the small molecules bind to a pocket in contact with the α7 helix on the opposite side of the molecule from the MIDAS domain [140][141][142][143][144][145] . This region has been previously shown to be important for ligand binding and receptor function [146][147] .…”

“…Lovastatin, a lipid-lowering drug that was found unexpectedly to inhibit binding of ICAM to α L, and the volatile anesthetic isoflurane have both been co-crystallized in this position 142,148 and both have been shown to inhibit immune functioning [149][150] .…”

Inhibition of ICAM-1/LFA-1-mediated heterotypic T-cell adhesion to epithelial cells: design of ICAM-1 cyclic peptides

“…For example, anti-ICAM-1 and anti-CD11a monoclonal antibodies (mAb) have been shown to inhibit T-cell adhesion mediated by LFA-1 and have been developed for the treatment of rheumatoid arthritis, insulin-dependent diabetes, and psoriasis. 5,6 Also, small organic molecules such as lovastatin, 7 p-arylthiocinnamides, and hydantoin derivatives (i.e., BRIT-377) 8,9 have been shown to inhibit ICAM-1/LFA-1 interactions by binding to the I-domain of LFA-1.…”