RESUMO
Phenotypic screens, in which chemical libraries are assayed on cells with the aim to isolate compounds that interfere with a given cell function, are a risky but powerful strategy to discover, in the same approach, new therapeutic targets and the compounds able to regulate them. With a strong experience of nearly 10 years in the field, we present the advantages of such an approach, the possible troubles and technical solutions. We also present in this paper a french network which has been recently built and that gather all the competencies needed for screening approaches.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Terapia de Alvo Molecular/métodos , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/farmacologia , Algoritmos , Avaliação Pré-Clínica de Medicamentos/instrumentação , França , Ensaios de Triagem em Larga Escala/instrumentação , Ensaios de Triagem em Larga Escala/métodos , Humanos , Fenótipo , Bibliotecas de Moléculas Pequenas/provisão & distribuiçãoRESUMO
Protein kinase CK2 is a multifunctional kinase of medical importance that is dysregulated in many cancers. In this study, polyoxometalates were identified as original CK2 inhibitors. [P2Mo18O62](6-) has the most potent activity. It inhibits the kinase in the nanomolar range by targeting key structural elements located outside the ATP- and peptide substrate-binding sites. Several polyoxometalate derivatives exhibit strong inhibitory efficiency, with IC50 values < or = 10 nM. Furthermore, these inorganic compounds show a striking specificity for CK2 when tested in a panel of 29 kinases. Therefore, polyoxometalates are effective CK2 inhibitors in terms of both efficiency and selectivity and represent nonclassical kinase inhibitors that interact with CK2 in a unique way. This binding mode may provide an exploitable mechanism for developing potent drugs with desirable properties, such as enhanced selectivity relative to ATP-mimetic inhibitors.
Assuntos
Caseína Quinase II/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Compostos de Tungstênio/farmacologia , Trifosfato de Adenosina/química , Sítios de Ligação , Química Farmacêutica/métodos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Peptídeos/química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Compostos de Tungstênio/químicaRESUMO
Protein-protein interactions have a key role in transduction pathways that regulate many cellular functions. Structural and functional properties of protein-protein interface are now better understood, therefore offering attractive opportunities for therapeutic intervention. Developping small molecules that modulate protein-protein interactions is challenging. Nethertheless, significant progress in this endeavour has been made on several fronts. Here, we use few illustrative examples to summarize recent work in this emerging field.