title: Nonpeptidic, monocharged, cell permeable ligands for the p56lck SH2 domain.
abstract: p56lck is a member of the src family of tyrosine kinases and plays a critical role in the signal transduction events that lead to T cell activation. Ligands for the p56lck SH2 domain have the potential to disrupt the interaction of p56lck with its substrates and derail the signaling cascade that leads to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEEI, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 1999, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the nonpeptidic, monocharged compound, 9S. This molecule displays good binding affinity for the p56lck SH2 domain (K(d) 1 microM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibitory effects on a very early event in T cell activation, namely calcium mobilization.
authors.affiliation: Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. jproudfo@rdg.boehringer-ingelheim.com
authors.forename: J R
authors.initials: JR
authors.lastname: Proudfoot
authors.forename: R
authors.initials: R
authors.lastname: Betageri
authors.forename: M
authors.initials: M
authors.lastname: Cardozo
authors.forename: T A
authors.initials: TA
authors.lastname: Gilmore
authors.forename: S
authors.initials: S
authors.lastname: Glynn
authors.forename: E R
authors.initials: ER
authors.lastname: Hickey
authors.forename: S
authors.initials: S
authors.lastname: Jakes
authors.forename: A
authors.initials: A
authors.lastname: Kabcenell
authors.forename: T M
authors.initials: TM
authors.lastname: Kirrane
authors.forename: A K
authors.initials: AK
authors.lastname: Tibolla
authors.forename: S
authors.initials: S
authors.lastname: Lukas
authors.forename: U R
authors.initials: UR
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Sharma
authors.forename: M
authors.initials: M
authors.lastname: Yazdanian
authors.forename: N
authors.initials: N
authors.lastname: Moss
authors.forename: P L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: D R
authors.initials: DR
authors.lastname: Cameron
authors.forename: J M
authors.initials: JM
authors.lastname: Ferland
authors.forename: J
authors.initials: J
authors.lastname: Gauthier
authors.forename: J
authors.initials: J
authors.lastname: Gillard
authors.forename: V
authors.initials: V
authors.lastname: Gorys
authors.forename: M
authors.initials: M
authors.lastname: Poirier
authors.forename: J
authors.initials: J
authors.lastname: Rancourt
authors.forename: D
authors.initials: D
authors.lastname: Wernic
authors.forename: M
authors.initials: M
authors.lastname: Llinas-Brunet
mesh_terms: D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018909:src Homology Domains
chemical_list: C431684:3-(2'-(dimethyl)naphthylacetylamino-3'-(4''-(1'''-carboxy-1'''-methyl)ethyl)benzene)propanoylamino-1-(4-methoxybenzyl)-4-methyl-2-pyridone; D008024:Ligands; D011728:Pyridones; D010649:Phenylalanine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium