RESUMO
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Experimental/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Pteridinas/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Flavinas , Perfilação da Expressão Gênica , Humanos , Leucemia Experimental/sangue , Leucemia Mieloide Aguda/sangue , Masculino , Camundongos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pteridinas/uso terapêutico , RNA/metabolismo , Motivo de Reconhecimento de RNA/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transcriptoma/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Silylenes are useful reactive intermediates for the stereoselective construction of compounds containing carbon-silicon bonds. Despite their synthetic utility, the development of either an enantioselective or diastereoselective metal-catalyzed silylene transfer reaction, in which ligands on the metal catalyst control stereoselectivity, has not been achieved. In this article, we report that the structure of the alkene is the most important for controlling stereoselectivity in these reactions. The stereochemical course of kinetically controlled silacyclopropanation reactions was not affected by the nature or chirality of the ligands on the metal. When silylene transfer reactions were reversible, however, products can be formed with a high degree of diastereoselectivity (90 : 10 d.r.).
RESUMO
Bent out of shape: Silver-catalyzed insertions of silylenes into propargylic CO bonds of epoxides regioselectively form 1,2-silaoxetanes, which add to aldehydes to give the title allenes as single diastereomers (see scheme; Ts=4-toluenesulfonyl). An X-ray crystal structure confirmed the stereochemistry of the allene, which is bent significantly from linearity (164°).
