7 research outputs found
A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.
With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.We also thank the Bill and Melinda Gates Foundation and the EU FP7 MM4TB Grant n°260872, the ERC-STG INTRACELLTB Grant n°260901, the Agence Nationale de la Recherche (ANR-10-EQPX-04-01), the Feder (12001407 (D-AL) Equipex Imaginex BioMed) and the Région Nord Pas de Calais, France, for providing funding to support this work.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C5OB02630
Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays
Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell <i>Mycobacterium tuberculosis</i> Assays
Small-molecule inhibitors
of the mycobacterial transcriptional
repressor EthR have previously been shown to act as boosters of the
second-line antituberculosis drug ethionamide. Fragment-based
drug discovery approaches have been used in the past to make highly
potent EthR inhibitors with ethionamide boosting activity both <i>in vitro</i> and <i>ex vivo</i>. Herein, we report
the development of fragment-sized EthR ligands with nanomolar minimum
effective concentration values for boosting the ethionamide
activity in <i>Mycobacterium tuberculosis</i> whole-cell
assays
A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters
Integrated Genomic Characterization of Papillary Thyroid Carcinoma
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of onco-miRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the diseaseclose6