RESUMEN
Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans. Heterobivalent BTK protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the BTK inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and in vitro characterization of BTK PROTACs based on the selective BTK inhibitor GDC-0853 and the cereblon recruitment ligand pomalidomide. PTD10 is a highly potent BTK degrader (DC50 0.5 nM) that inhibited cell growth and induced apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.
Asunto(s)
Linfocitos B , Proteínas Tirosina Quinasas , Quimera Dirigida a la Proteólisis , Humanos , Agammaglobulinemia Tirosina Quinasa , Linfocitos B/metabolismo , Proliferación Celular , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quimera Dirigida a la Proteólisis/química , Quimera Dirigida a la Proteólisis/farmacologíaRESUMEN
A facile synthetic procedure for the preparation of α-trifluoromethyl carboxylic acids and esters was achieved through multicomponent coupling reactions between gem-difluoroalkenes, cesium fluoride, and carbon dioxide. The products were generated in moderate to excellent yields, and the synthetic utility of this method was demonstrated through the preparation of trifluoromethylated versions of popular nonsteroidal anti-inflammatory drugs (NSAIDs).
