title: A conformationally fixed analog of the peptide mimic Grb2-SH2 domain: synthesis and evaluation against the A431 cancer cell.
abstract: A small peptide mimic of the Grb2-SH2 domain, which was previously prepared through the template-assisted click approach and exhibited selective A431 tumor growth inhibition both in vitro and in vivo, was further elaborated on to enhance the interaction with target phosphorylated proteins. A conformationally fixed analog was efficiently synthesized by solid-supported ring-closing metathesis and Cu(i)/His-mediated self-activating Huisgen [3+2] cycloadditon as the key steps, and exhibited a 10-fold enhanced affinity to a phosphorylated peptide, a truncated peptide analog of the Grb2-SH2-interacting phosphoproteins. A stronger interaction with the target phosphorylated proteins gave this cyclic analog cytotoxic activity in A431 cells.
authors: Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka-shi, Osaka 560-0043, Japan.
authors: Takayuki
authors: T
authors: Iwata
authors: Katsunori
authors: K
authors: Tanaka
authors: Tsuyoshi
authors: T
authors: Tahara
authors: Satoshi
authors: S
authors: Nozaki
authors: Hirotaka
authors: H
authors: Onoe
authors: Yasuyoshi
authors: Y
authors: Watanabe
authors: Koichi
authors: K
authors: Fukase
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D051380:GRB2 Adaptor Protein / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D018716:Molecular Mimicry; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains
chemical_list: D051380:GRB2 Adaptor Protein; D010455:Peptides; D010456:Peptides, Cyclic; D010750:Phosphoproteins