The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

Qin, An; Jin, Hua; Yu, Shizhu; Gao, Yun; Chen, Yifan; Zhou, Li-Na; Wang, Shusheng; Lu, Xiao‐Jie

doi:10.1038/s41419-020-03015-6

Cited by 38 publications

(29 citation statements)

References 52 publications

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“…BRD4 is degraded by PROTACs to overcome BETi resistance caused by BRD4 stability (114,115) (Figure 2). It has been confirmed that PROTACs can effectively induce the degradation of BRD4 and are more effective than corresponding BRD4 inhibitors in inhibiting the growth of tumor cells and promoting cell apoptosis (116,117).…”

Section: Targeting Brd4 Modification Pathway For Disease Treatmentmentioning

confidence: 93%

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

et al. 2022

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Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.

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Section: Targeting Brd4 Modification Pathway For Disease Treatmentmentioning

confidence: 93%

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

et al. 2022

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“…To explore the role of cooperativity in ternary complex formation, the Ciulli group studied PROTAC-induced degradation of the BET protein family (BRD2, BRD3, BRD4) ( 83 ), a protein family extensively studied in the PROTAC field ( 27 , 60 , 73 , 74 , 81 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ). Using SPR and ITC, they found that ternary complexes with positive cooperativity (BRD4 BR2 :PROTAC MZ1:VHL; α = 22) caused more efficient cellular degradation than complexes with negative cooperativity (BRD4 BR2 :PROTAC MP61:VHL; α = 0.2).…”

Section: Hijacking Of the Ups: Protacsmentioning

confidence: 99%

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Alabi

Crews

2021

Journal of Biological Chemistry

157

122

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Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality. By co-opting protein degradation pathways, TPD facilitates complete removal of the protein molecules from within or outside the cell. While the pioneering Proteolysis-Targeting Chimera (PROTAC) technology and molecular glues hijack the ubiquitin-proteasome system, newer modalities co-opt autophagy or the endo-lysosomal pathway. Using this mechanism, TPD is posited to largely expand the druggable space far beyond small-molecule inhibitors. In this review, we discuss the major advances in TPD, highlight our current understanding, and explore outstanding questions in the field.

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“…Minko[ 82 ] reported a similar anticancer activity of ARV-825 in pancreatic cancer and this activity exhibited in both 2D cell culture and 3D multicellular tumor spheroid models. Additionally, Qin et al [ 83 ] showed that A1874 down-regulated c-MYC, Bcl-2, and cyclin D1 in colon cancer cells and had an anti-colon cancer activity by inhibiting cell proliferation, invasion and migration. Strikingly, A1874 presented to be much more effective than other BET inhibitors including JQ1 and I-BET151.…”

Section: New Bet Inhibitors Using Protac Technologymentioning

confidence: 99%

Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers

Sun¹,

Du²,

Li³

et al. 2022

WJGO

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Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.

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The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

Cited by 38 publications

References 52 publications

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers

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