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Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase.
Leonard, D M; Shuler, K R; Poulter, C J; Eaton, S R; Sawyer, T K; Hodges, J C; Su, T Z; Scholten, J D; Gowan, R C; Sebolt-Leopold, J S; Doherty, A M.
Afiliación
  • Leonard DM; Department of Chemistry, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. leona01@aa.wl.com
J Med Chem ; 40(2): 192-200, 1997 Jan 17.
Article en En | MEDLINE | ID: mdl-9003517
Mutational activation of ras has been found in many types of human cancers, including a greater than 50% incidence in colon and about 90% in pancreatic carcinomas. The activity of both native and oncogenic ras proteins requires a series of post-translational processing steps. The first event in this process is the farnesylation of a cysteine residue located in the fourth position from the carboxyl terminus of the ras protein, catalyzed by the enzyme farnesyltransferase (FTase). Inhibitors of FTase are potential candidates for development as antitumor agents. Through a high-volume screening program, the pentapeptide derivative PD083176 (1), Cbz-His-Tyr(OBn)-Ser(OBn)-Trp-DAla-NH2, was identified as an inhibitor of rat brain FTase, with an IC50 of 20 nM. Structure-activity relationships were carried out to determine the importance of the side chain and chirality of each residue. This investigation led to a series of potent FTase inhibitors which lack a cysteine residue as found in the ras peptide substrate. The parent compound (1) inhibited the insulin-induced maturation of Xenopus oocytes (concentration: 5 pmol/oocyte), a process which is dependent on the activation of the ras pathway.
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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oligopéptidos / Transferasas / Transferasas Alquil y Aril / Cisteína / Inhibidores Enzimáticos Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 1997 Tipo del documento: Article País de afiliación: Estados Unidos
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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oligopéptidos / Transferasas / Transferasas Alquil y Aril / Cisteína / Inhibidores Enzimáticos Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 1997 Tipo del documento: Article País de afiliación: Estados Unidos