RESUMO
DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin-RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.
Assuntos
Antifibróticos , Descoberta de Drogas , Inibidores Enzimáticos , Fibrose , Cardiopatias , Peptídeos e Proteínas de Sinalização Intracelular , Pirimidinas , Enzimas de Conjugação de Ubiquitina , Animais , Masculino , Camundongos , Ratos , Antifibróticos/química , Antifibróticos/farmacologia , Proteínas Culina/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Cardiopatias/tratamento farmacológico , Cardiopatias/metabolismo , Cardiopatias/patologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Proteína NEDD8/metabolismo , Pirimidinas/química , Ratos Sprague-Dawley , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , UbiquitinasRESUMO
CBP/p300, functioning as histone acetyltransferases and transcriptional co-factors, represents an attractive target for various diseases, including malignant tumor. The development of small-molecule inhibitors targeting the bromodomain and HAT domains of CBP/p300 has aroused broad interests of medicinal chemist in expectation of providing new hope for anti-cancer treatment. In particular, the CBP/p300 bromodomain inhibitor CCS1477, identified by CellCentric, is currently undergone clinical evaluation for the treatment of haematological malignancies and prostate cancer. In this review, we depict the development of CBP/p300 inhibitors reported from 2010 to 2020 and particularly highlight their structure-activity relationships (SARs), binding modes, selectivity and pharmacological functions with the aim to facilitate rational design and development of CBP/p300 inhibitors.
