更新于：2024-11-01

EP300 x BET x CREBBP

更新于：2024-11-01

基本信息

关联

项与 EP300 x BET x CREBBP 相关的药物

CN470

靶点

BET x CREBBP x EP300

作用机制

BET抑制剂 [+2]

在研机构

Kyoto Pharmaceutical University

原研机构

Kyoto Pharmaceutical University

在研适应症

急性淋巴细胞白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 EP300 x BET x CREBBP 相关的临床结果

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100 项与 EP300 x BET x CREBBP 相关的转化医学

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0 项与 EP300 x BET x CREBBP 相关的专利（医药）

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项与 EP300 x BET x CREBBP 相关的文献（医药）

2024-10-03·NAR Cancer

RNA kinetics influence the response to transcriptional perturbation in leukaemia cell lines

Article

作者: Bjelosevic, Stefan ; Kong, Isabella Y ; Feran, Breon ; Hawkins, Edwin D ; Rivera, Sarahi ; Yoannidis, David ; Zethoven, Magnus ; Vervoort, Stephin J ; Papenfuss, Anthony T ; Fan, Zheng ; Todorovski, Izabela ; Johnstone, Ricky W ; Arnau, Gisela Mir ; Simpson, Kaylene J ; Voulgaris, Olivia ; Gadipally, Sreeja ; Tsang, Mary-Jane

AbstractTherapeutic targeting of dysregulated transcription has emerged as a promising strategy for the treatment of cancers, such as leukaemias. The therapeutic response to small molecule inhibitors of Bromodomain-Containing Proteins (BRD), such as BRD2 and BRD4, P300/cAMP-response element binding protein (CBP) and Cyclin Dependent Kinases (CDKs), is generally attributed to the selective disruption of oncogenic gene expression driven by enhancers, super-enhancers (SEs) and lineage-specific transcription factors (TFs), including the c-MYC oncogene. The selectivity of compounds targeting the transcriptional machinery may be further shaped by post-transcriptional processes. To quantitatively assess the contribution of post-transcriptional regulation in responses to transcription inhibition, we performed multi-omics analyses to accurately measure mRNA production and decay kinetics. We demonstrate that it is not only the selective disruption of mRNA production, but rather mRNA decay rates that largely influence the selectivity associated with transcriptional inhibition. Accordingly, genes down-regulated with transcriptional inhibitors are largely characterized by extremely rapid mRNA production and turnover. In line with this notion, stabilization of the c-MYC transcript through swapping of its 3′ untranslated region (UTR) rendered c-MYC insensitive to transcriptional targeting. This failed to negate the impact on c-MYC downstream targets and did not abrogate therapeutic responses. Finally, we provide evidence that modulating post-transcriptional pathways, such as through ELAVL1 targeting, can sensitize long-lived mRNAs to transcriptional inhibition and be considered as a combination therapy approach in leukaemia. Taken together, these data demonstrate that mRNA kinetics influence the therapeutic response to transcriptional perturbation and can be modulated for novel therapeutic outcomes using transcriptional agents in leukaemia.

2023-09-01·Experimental Cell Research

BET inhibitors induce NF-κB and E2F downregulation in Hodgkin and Reed–Sternberg cells

Article

作者: Estévez, Mónica ; García, Juan F ; Rita, Claudia G ; Díaz, Eva ; Montalbán, Carlos ; Fernández, Sara

The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed-Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.

2021-07-22·Journal of Medicinal Chemistry1区 · 医学

Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain

1区 · 医学

Article

作者: Bolland, Hannah ; Biggin, Philip C. ; Brand, Michael ; Laurin, Corentine M. C. ; See, Larissa ; Chan, Anthony K. N. ; Paton, Robert S. ; Filippakopoulos, Panagis ; Andrews, Katrina H. ; Moroglu, Mustafa ; Skwarska, Anna ; Hammond, Ester M. ; Picaud, Sarah ; Christensen, Kirsten E. ; Scorah, Amy R. ; Bluck, Joseph P. ; Rooney, Timothy P. C. ; Pomerantz, William C. K. ; Vinh, Kayla B. ; Conway, Stuart J. ; Fedorov, Oleg ; Cortopassi, Wilian A. ; Perell, Gabriella ; Cooper, Richard I. ; Heitel, Pascal ; Clayton, James ; Kalra, Prakriti ; Schiedel, Matthias

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O₂), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.