Ligands for the tyrosine kinase p56(lck) SH2 domain: Discovery of potent dipeptide derivatives with monocharged, nonhydrolyzable phosphate replacements

• Published in: Journal of medicinal chemistry Vol. 42; no. 10; pp. 1757 - 1766
• Main Authors: Beaulieu, PL, Cameron, DR, Ferland, JM, Gauthier, J, Ghiro, E, Gillard, J, Gorys, Poirier, M, Rancourt, J, Wernic, D, Llinas-Brunet, M, Betageri, R, Cardozo, M, Hickey, ER, Ingraham, R, Jakes, S, Kabcenell, A, Kirrane, T, Lukas, S, Patel, U, Proudfoot, J, Sharma, R, Tong, L, Moss, N
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 20.05.1999
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; SIGNAL-TRANSDUCTION; PHOSPHORYLATED PEPTIDES; BINDING-SPECIFICITY; INHIBITORY PEPTIDES; SEMIEMPIRICAL METHODS; SRC HOMOLOGY-2 DOMAINS; CRYSTAL-STRUCTURES; SURFACE-PLASMON RESONANCE; AFFINITY PHOSPHOTYROSYL PEPTIDE; STRUCTURE-BASED DESIGN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980676t

p56(lck) is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56(lck) promotes phosphotyrosine-dependent protein-protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56(lck) SH2 domain, we have designed novel dipeptides that contain monocharged, nonhydrolyzable phosphate group replacements and bind to the protein with K-D's in the low micromolar range. Replacement of the phosphate group in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged ligands, with 83- and 233-fold decreases in potency, respectively. This loss in binding affinity can be partially compensated for by incorporating large lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold increases in potency depending on the nature of the phosphate replacement. The discovery of potent (2-3 mu M), hydrolytically stable dipeptide derivatives, bearing only two charges at physiological pH, represents a significant step toward the discovery of compounds with cellular activity and the development of novel therapeutics for conditions associated with undesired T-cell proliferation.