Structure-activity relationship studies of a series of peptidomimetic ligands for alpha(4) beta(1) integrin on Jurkat T-leukemia cells.
alpha(4)beta(1) integrin is a therapeutic target for inflammation, autoimmune diseases, and lymphoid cancers. A series of peptidomimetic ligands based on the Nle-D-I motif have been synthesized and their binding affinities (IC(50)) to activated alpha(4)beta(1) integrin on Jurkat T-leukemia cells have been determined using a cell adhesion assay. One of the 51 ligands, 18, has been determined to have an IC(50) of 0.6 nM and has a more than twofold increase of binding affinity than the initial lead compound 1. Extensive SAR studies provide important information for further ligand optimization, which has served as a foundation for studies that ultimately led to identification of a potent ligand with an IC(50) of 2 pM.
Liu
Ruiwu
R
Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Cancer Center, University of California Davis, 4501 X Street, Sacramento, CA 95817, USA. rwliu@ucdavis.edu
Peng
Li
L
Han
Huijun
H
Lam
Kit S
KS
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001681:Biological Assay; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D019169:Jurkat Cells; D008024:Ligands; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D039041:Integrin alpha4beta1; D008024:Ligands; D010455:Peptides