RESUMO
The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.
Assuntos
Descoberta de Drogas , Receptores Nucleares Órfãos/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Ligantes , Receptores X do Fígado , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , BenzenossulfonamidasRESUMO
The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
Assuntos
PPAR delta/agonistas , PPAR gama/agonistas , Tiazóis/química , Animais , Simulação por Computador , Cristalografia por Raios X , PPAR delta/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
PPM1D encodes WIP1, a serine-threonine phosphatase that had previously been shown to be the driver oncogene of a 17q23 amplicon that is present in approximately 15% of human breast tumors. However, it is unknown whether it has any role in the remaining 85% of breast tumors. A recent study using Wip1-deficient mice revealed that blocking its function significantly impaired RAS and ERBB2-induced breast tumor formation, suggesting that the inhibition of Wip1 could be a broad-spectrum treatment for breast cancer. However, because of the structure of Wip1, the development of small molecule inhibitors is a significant challenge.
Assuntos
Neoplasias da Mama/prevenção & controle , Proteínas de Neoplasias/fisiologia , Fosfoproteínas Fosfatases/fisiologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Genes ras/fisiologia , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/deficiência , Fosfoproteínas Fosfatases/deficiência , Proteína Fosfatase 2C , Receptor ErbB-2/metabolismoRESUMO
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.