RESUMO
The keloid lesion is recognised as a spatially heterogeneous mass both in cellular and acellular composition and biological activity. Here, we have utilised a bioinformatic approach to determine whether this spatial heterogeneity is also evident at the molecular level and to identify key upstream regulators of signalling pathways enriched in the lesion in a spatially-restricted manner. Differentially expressed genes (20% change, p < 0.05) obtained from microarray datasets derived from whole keloid biopsies and ex vivo-cultured keloid fibroblasts, both from distinct regions of the keloid lesion (leading edge, centre, and top) have been analysed to show that the TGFß family plays a significant but spatially dependent role in regulation of keloid gene expression. Furthermore, we have identified additional upstream signalling molecules involved in driving keloid biology and provide information on therapeutic targets whose modulation might be expected to lead to significant therapeutic efficacy.
Assuntos
Fibroblastos/metabolismo , Queloide/genética , Fator de Crescimento Transformador beta/genética , Biópsia , Células Cultivadas , Biologia Computacional , Expressão Gênica , Humanos , Análise de Componente Principal , Transdução de SinaisRESUMO
The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Benzamidas/sangue , Benzamidas/química , Compostos de Bifenilo/sangue , Compostos de Bifenilo/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Conformação Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/química , RatosRESUMO
p38alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFalpha and IL-1beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38alpha/beta inhibitors using crystal structures of our inhibitors bound to p38alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.