RESUMO
There is today a blatant need for new antifungal agents, because of the recent increase in life-threatening infections involving an ever-greater number of fungal strains. Fungi make extensive use of kinases in the regulation of essential processes, in particular the cell cycle. Most fungal kinases, however, are shared with higher eukaryotes. Only the kinases which have no human homologs, such as the histidine kinases, can be used as targets for antifungal drugs design. This review describes efforts directed towards the discovery of drugs active against a novel target, the atypical cell cycle kinase, Civ1.
Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Quinases Ciclina-Dependentes , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Purinas/química , Purinas/farmacologia , Sequência de Aminoácidos , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Fungos/efeitos dos fármacos , Fungos/enzimologia , Fungos/fisiologia , Modelos Moleculares , Dados de Sequência Molecular , Relação Estrutura-Atividade , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
Protein kinases (Ser/Thr and Tyr) play a key role in signal transduction pathways. It has been shown that deregulation of the Cdk activity is linked to cell proliferation and cancer. Inhibition of cyclin-dependent kinases (Cdks) is an important target for potential new anti-cancer drugs. Following the discovery of Olomoucine, a wide range of tri-substituted purine derivatives have been synthesized, leading to potent Cdk inhibitors. These purine-derived compounds bind to the ATP pocket of the protein. Of interest for structure-based drug design, the different crystal structures published to date show evidence for three different binding modes for the purine ring, allowing diverse exploration of the ATP binding site. Some examples of synthesis and structure activity relationships are discussed for a set of purine derivatives, tri-substituted on C-2, N-9 and C-6. Finally, in vivo activities are reviewed, as well as the applications in other therapeutic areas.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Purinas/química , Purinas/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Ciclo Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Quinases Ciclina-Dependentes/classificação , Quinases Ciclina-Dependentes/metabolismo , Humanos , Modelos Moleculares , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Life-threatening fungal infections are becoming more frequent and involve a greater variety of strains, many of which are drug-resistant. Both public research organisations and the pharmaceutical industry are committed to the development of new drugs to satisfy this increasing medical need. The approach described here exemplifies the efforts directed towards the discovery of drugs which are active against novel targets, exemplified by the cell-cycle regulator, Civ1.