title: Design of tetrapeptide ligands as inhibitors of the Src SH2 domain.
abstract: Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide pTyr-Glu-Glu-Ile (pYEEI) binds to Src SH2 domain with high affinity (K(d)=100 nM). The development of five classes of tetrapeptides as inhibitors for the Src SH2 domain is described. Peptides were prepared via solid-phase peptide synthesis and tested for affinity to Src SH2 domain using a fluorescence polarization based assay. All of the N-terminal substituted pYEEI derivatives (class II) presented binding affinity (IC(50)=of 2.7-8.6 microM) comparable to pYEEI (IC(50)=6.5 microM) in this assay. C-Terminal substituted pYEEI derivatives (class III) showed a lower binding affinity with IC(50) values of 34-41 microM. Amino-substituted phenylalanine derivatives (class IV) showed weak binding affinities (IC(50)=16-153 microM). Other substitutions on phenyl ring (class I) or the replacement of the phenyl ring with other cyclic groups (class V) dramatically decreased the binding of tetrapeptides to Src SH2 (IC(50)>100 microM). The ability of pYEEI and several of the tetrapeptides to inhibit the growth of cancer cells were assessed in a cell-based proliferation assay in human embryonic kidney (HEK) 293 tumor cells. The binding affinity of several of tested compounds against Src SH2 domain correlates with antiproliferative activity in 293T cells. None of the compounds showed any significant antifungal activity against Candida albicans ATCC 14053 at the maximum tested concentration of 10 microM. Overall, these results provided the structure-activity relationships for some FEEI and YEEI derivatives designed as Src SH2 domain inhibitors.
authors.affiliation: Department of Biomedical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Nguyen-Hai
authors.initials: NH
authors.lastname: Nam
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Pitts
authors.forename: Gongqin
authors.initials: G
authors.lastname: Sun
authors.forename: Soroush
authors.initials: S
authors.lastname: Sardari
authors.forename: Amie
authors.initials: A
authors.lastname: Tiemo
authors.forename: Mingxing
authors.initials: M
authors.lastname: Xie
authors.forename: Bingfang
authors.initials: B
authors.lastname: Yan
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008314:Malonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D000577:Amides; D000935:Antifungal Agents; D008024:Ligands; D008314:Malonates; D009842:Oligopeptides; D010756:Phosphoric Acids; C030290:malonic acid; C011067:phosphoramidic acid; D016392:Proto-Oncogene Proteins pp60(c-src)