Bromodomain PHD-finger transcription factor(BPTF)is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone ...Bromodomain PHD-finger transcription factor(BPTF)is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation.BPTF is also involved in oncogene transcription in diverse progressions of cancers.Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers,no potent and selective inhibitor targeting the BPTF bromodomain has been discovered.In this study,we identified a potential inhibitor,namely,C620-0696,by computational docking modeling to target bromodomain.Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain.Moreover,C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer(NSCLC)cells.It suppressed the expression of the BPTF target gene c-MYC,which is known as an oncogenic transcriptional regulator in various cancers.C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage.Thus,our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules,supporting further exploration of the use of these inhibitors in oncology.展开更多
Cat's eye syndrome chromosome candidate 2 bromodomain(CECR2 BRD)and Bromodomain PHD transcription factor bromodomain(BPTF BRD)are the same subfamily proteins,both of which are highly conserved in sequence and bind...Cat's eye syndrome chromosome candidate 2 bromodomain(CECR2 BRD)and Bromodomain PHD transcription factor bromodomain(BPTF BRD)are the same subfamily proteins,both of which are highly conserved in sequence and binding pockets.Challenges remain in the development of small molecules to inhibit one of the two bromodomains(BRDs),in view of each subtype may possess unique physiological and pathological functions.There is still a lack of effective selective inhibitors of CECR2 BRD,which makes it difficult to fully understand the pathogenesis of CECR2-BRD in diseases,especially cancers.Herein,we report our efforts to discover a series of highly selective CECR2 BRD inhibitors over BPTF BRD based on TP-248.Structure-based molecular optimization led to the discovery of DC-CEi-26,whose IC_(50) for CECR2 BRD was 96.7±14.9 nmol/L and selectivity was up to 590×over BPTF BRD.DC-CEi-26 showed weak potencies for other classic BRDs in different subfamily,which may serve as a chemical probe for CECR2 BRD biological research.展开更多
基金supported by Macao Science and Technology Development Fund(Nos.102/2016/A3,130/2017/A3,0003/2018/A1,and 046/2016/A2).
文摘Bromodomain PHD-finger transcription factor(BPTF)is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation.BPTF is also involved in oncogene transcription in diverse progressions of cancers.Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers,no potent and selective inhibitor targeting the BPTF bromodomain has been discovered.In this study,we identified a potential inhibitor,namely,C620-0696,by computational docking modeling to target bromodomain.Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain.Moreover,C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer(NSCLC)cells.It suppressed the expression of the BPTF target gene c-MYC,which is known as an oncogenic transcriptional regulator in various cancers.C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage.Thus,our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules,supporting further exploration of the use of these inhibitors in oncology.
基金the Science and Technology Commission of Shanghai Municipality(Y811298033 to Q.L.,and 19XD1404700 to C.L.)the scientific research innovation program“Xiyuanjiang River Scholarship”of the College of Life Sciences,Fujian Normal University+3 种基金the State Key Laboratory of Drug Research(SIMM2105KF-07toH.L.)Fujian Provincial Natural Science Foundation(2021J01203 to H.L.)the Natural Science Foundation of Fujian Province(2019J05073 to J.L.)the Joint Funds forthe Innovation of Science and Technology of Fujian Province(2018Y9071 to J.L.).
文摘Cat's eye syndrome chromosome candidate 2 bromodomain(CECR2 BRD)and Bromodomain PHD transcription factor bromodomain(BPTF BRD)are the same subfamily proteins,both of which are highly conserved in sequence and binding pockets.Challenges remain in the development of small molecules to inhibit one of the two bromodomains(BRDs),in view of each subtype may possess unique physiological and pathological functions.There is still a lack of effective selective inhibitors of CECR2 BRD,which makes it difficult to fully understand the pathogenesis of CECR2-BRD in diseases,especially cancers.Herein,we report our efforts to discover a series of highly selective CECR2 BRD inhibitors over BPTF BRD based on TP-248.Structure-based molecular optimization led to the discovery of DC-CEi-26,whose IC_(50) for CECR2 BRD was 96.7±14.9 nmol/L and selectivity was up to 590×over BPTF BRD.DC-CEi-26 showed weak potencies for other classic BRDs in different subfamily,which may serve as a chemical probe for CECR2 BRD biological research.
