RESUMEN
Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Resistencia a Antineoplásicos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Docetaxel/farmacología , Docetaxel/uso terapéutico , Sinergismo Farmacológico , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Complejo Represivo Polycomb 2/química , Complejo Represivo Polycomb 2/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Survivin/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Proteins found in nature have traditionally been the most frequently used biocatalysts to produce numerous natural products ranging from commodity chemicals to pharmaceuticals. Protein engineering has emerged as a powerful biotechnological toolbox in the development of metabolic engineering, particularly for the biosynthesis of natural products. Recently, protein engineering has become a favored method to improve enzymatic activity, increase enzyme stability, and expand product spectra in natural product biosynthesis. This review summarizes recent advances and typical strategies in protein engineering, highlighting the paramount role of protein engineering in improving and diversifying the biosynthesis of natural products. Future prospects and research directions are also discussed.
