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1.
J Med Chem ; 64(21): 16213-16241, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34714078

RESUMO

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.


Assuntos
Imidazóis/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Piridinas/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismo
2.
Diabetes ; 55(5): 1190-6, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16644672

RESUMO

The glucoincretin hormone glucagon-like peptide-1 (GLP-1) increases pancreatic beta-cell proliferation and survival through sequential activation of the epidermal growth factor receptor (EGFR), phosphatidylinositol-3 kinase (PI 3-kinase), and Akt. We investigated the role of transcription factor FoxO1 in the proliferative and antiapoptotic actions of GLP-1 in beta-cells. GLP-1 inhibited FoxO1 through phosphorylation-dependent nuclear exclusion in pancreatic beta (INS832/13) cells. The effect of GLP-1 was suppressed by inhibitors of EGFR (AG1478) and PI 3-kinase (LY294002). In contrast, LY294002 but not AG1478 suppressed insulin-induced FoxO1 phosphorylation. Expression of constitutively nuclear FoxO1 in beta-cells prevented the proliferative and antiapoptotic actions of GLP-1 in cultured beta-cells and the increase in pancreatic beta-cell mass in response to Exendin4 in transgenic mice. Gene expression and chromatin immunoprecipitation assays demonstrated that GLP-1 increases pancreatic and duodenal homeobox gene-1 and Foxa2 expression and inhibits FoxO1 binding to both promoters. We propose that FoxO1 mediates the pleiotropic effects of the glucoincretin hormone on cell proliferation and survival.


Assuntos
Fatores de Transcrição Forkhead/fisiologia , Peptídeos Semelhantes ao Glucagon/farmacologia , Glucagon/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Divisão Celular , Linhagem Celular , Sobrevivência Celular , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Peptídeo 1 Semelhante ao Glucagon , Glucose/fisiologia , Proteínas de Fluorescência Verde/genética , Insulina/farmacologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/fisiologia , Camundongos , Camundongos Transgênicos
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