RESUMEN
A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided.
Asunto(s)
Antineoplásicos/farmacología , Modelos Biológicos , Proteínas de Neoplasias/genética , Oncogenes , Bibliotecas de Moléculas Pequeñas/farmacología , Antineoplásicos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Proteínas de Neoplasias/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Structure-activity relationships of aryl alkynyl synergists of the general formula of Ar-Q-R, where Q represents a bridging structure, were studied using a standardised testing system and Relative Potency values. Ethers, esters, oxime ethers, amides and amines were prepared and evaluated. The length of the R-alkynyl chain, the role of the bridge and the substitution of the aromatic ring were examined systematically. The most potent compounds possessed an aromatic ring connected via a bridge of three atoms to an alkynyl chain, forming together a linear side-chain of six atoms. Several highly potent compounds were synthesised of which one (MB-599; proposed common name verbutin) was selected for development as a selective insecticide synergist in crop protection. Its high potential at practical insecticide:synergist ratios makes possible the reduction of the total amount of insect-control chemicals applied, and its use as an additive to produce new formulations of existing insecticides makes it highly advantageous in resistance management, giving a new tool to sustain the effectiveness of a wide range of insecticides. A product containing a (1+1) mixture of verbutin and beta-cypermethrin was launched in Hungary in 2002.