RESUMEN
Maternal embryonic leucine zipper kinase (MELK) is involved in several key cellular processes and displays increased levels of expression in numerous cancer classes (colon, breast, brain, ovary, prostate and lung). Although no selective MELK inhibitors have yet been approved, increasing evidence suggest that inhibition of MELK would constitute a promising approach for cancer therapy. A weak high-throughput screening hit (17, IC50â¯≈â¯5⯵M) with lead-like properties was optimized for MELK inhibition. The early identification of a plausible binding mode by molecular modeling offered guidance in the choice of modifications towards compound 52 which displayed a 98â¯nM IC50. A good selectivity profile was achieved for a representative member of the series (29) in a 486 protein kinase panel. Future elaboration of 52 has the potential to deliver compounds for further development with chemotherapeutic aims.
Asunto(s)
Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Tiofenos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 InhibidoraRESUMEN
Trityl group, Tr, is a molecular dynamic rotor of which the conformation and helicity depend on other groups in the close vicinity. Interactions with another covalently linked Tr group and with other substituents are analyzed in terms of transfer of chirality to the trityl group. Two trityl groups in a molecule can mutually interact at a distance of two, three, or five bonds. Despite its size, a Tr group attached to a cyclohexane or cyclopentane ring through an oxygen or nitrogen atom adopts either an axial or equatorial position, depending on additional stabilizing interactions, such as hydrogen bonding.