RESUMEN
Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.
Asunto(s)
Antineoplásicos , Neoplasias , Ratas , Animales , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met , Diseño de Fármacos , Adenosina Trifosfato , Antineoplásicos/farmacologíaRESUMEN
A transcriptional regulatory network (TRN) is a complex network composed of all of the regulatory interactions between transcription factors and the corresponding target genes. Recently, three-dimensional (3D) genomic studies have shown that the 3D structure of the genome may influence the regulation of gene transcription, which provides us with a novel perspective. In the present study, we constructed the TRN of the budding yeast Saccharomyces cerevisiae and placed it in the context of a 3D genome model. We analyzed the spatial organization of the yeast TRN on four levels: global features, central nodes, hierarchical structure and network motifs. The results obtained suggest that the TRN of S. cerevisiae presents an optimized structure in space to adapt to functional requirements.
Asunto(s)
Redes Reguladoras de Genes , Saccharomyces cerevisiae/genética , Perfilación de la Expresión Génica , GenómicaRESUMEN
In the title complex, [Na(C(2)HCl(2)O(3)S(2))(C(10)H(20)O(5))], there are two independent complex units in the asymmetric unit, one of which has a 55:45% disorder in the 15-crown-5 component. The coordination sphere about the Na atom in each complex unit comprises five bonds to O atoms of the crown ether [Na-O = 2.390â (7)-2.466â (6)â Å] and one to a thio-sulfate O atom [Na-O = 2.305â (4) and 2.447â (3)â Å].
