Bromodomain inhibitors and therapeutic applications

Gajjela, Bharath Kumar; Zhou, Ming-Ming

doi:10.1016/j.cbpa.2023.102323

Cited by 25 publications

(8 citation statements)

References 138 publications

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“…Over the past decade, there has been substantial effort to develop small molecule inhibitors of the BRD proteins as anti-cancer agents. [29][30][31][32] To date, all molecules that have entered clinical trials target the bromodomains, BD1 and BD2. A recent study, however, identified fragments that weakly engage the extraterminal (ET) domain.…”

Section: Resultsmentioning

confidence: 99%

mRNA display in cell lysates enables identification of cyclic peptides targeting the BRD3 extraterminal domain

Hurd,

Bush,

Powell

et al. 2024

Preprint

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mRNA display is a powerful technology to screen libraries of >1012cyclic peptides against a protein target, enabling the rapid discovery of high affinity ligands. These cyclic peptides are particularly well suited to challenging protein targets that have been difficult to drug with small molecules. However, target choice can still be limited as screens are typically performed against purified proteins which often demands the use of isolat-ed domains and precludes the use of aggregation-prone targets. Here, we report a method to perform mRNA display selections in mammalian cell lysates without the need for prior target purification, vastly expanding the potential target scope of mRNA display. We have applied the methodology to identify low to sub-nanomolar peptide binders for two targets; a NanoLuc subunit (LgBiT) and full-length bromodomain-containing protein 3 (BRD3). Our cyclic peptides for BRD3 were found to bind to the extraterminal (ET) do-main of BRD3 and the closely related BRD proteins, BRD2 and BRD4. While many chemical probes exist for the bromodomains of BRD proteins, the ET domain is relatively underexplored, making these peptides valu-able additions to the BRD toolbox.

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Section: Resultsmentioning

confidence: 99%

mRNA display in cell lysates enables identification of cyclic peptides targeting the BRD3 extraterminal domain

Hurd,

Bush,

Powell

et al. 2024

Preprint

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Section: Discussionmentioning

confidence: 99%

“…The clinically relevant inhibitors of epigenetic regulators like histone deacetylases (HDAC)s ( 28, 29 ) and DNA methyltransferases (DNMT) (30) , Histone Methyltransferases (HMTs) (31) , Histone Demethylase (HDMs) (32) , Bromodomain and Extra-Terminal (BET) (33) are well documented. The DNMT inhibitor (DNMTi) and HDAC inhibitor (HDACi) and BET inhibitors (BETi) has already been approved as drugs against selective cancers and entered market for clinical use (34) .…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Nalla,

Chatterjee,

Poyya

et al. 2024

Preprint

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Histone methyltransferases are selectively catalyzing the methylation of lysine or arginine residues of target histone and non-histone proteins, classified as lysine methyltransferases and arginine methyltransferases. The EZH2 and PRMT5 catalyze trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3 respectively. These histone repressive marks have been considered as hallmarks in cancer. Both PRMT5 and EZH2 over expressed in several cancers and have been considered as important target of drug development. As a result, many synthetic molecules as inhibitors of both PRMT5 and EZH2 are at different level of preclinical and clinical phases. Cancer atlas data analysis revealed that both PRMT5 and EZH2 had shown more than 90% amplification in breast cancer alone. We screened an array of phytocompounds towards the inhibition of PRMT5 and EZH2 usingin silico, in vitroassays. Among them Epigallocatechin-3-gallate (EGCG) has interacted with human PRMT5: MEP50 and EZH2 efficiently. The EGCG interacted within the SAM binding site, with a π-cation interaction at Lys 333 and H-bonds with Tyr324, Tyr334, Gly365, Leu437, and Glu444. Surface plasmon resonance analysis revealed that EGCG has strong binding affinity in nanomolar concentrations with both PRMT5-MEP50 than EZH2. Further in vitro methylation and cell-based assays proved the inhibitory potential of EGCG by reducing the catalytic products of PRMT5 and EZH2 i.e., H4R3me2s & H3K27me3 respectively and showed that it induced autophagy and apoptosis. Furthermorein vivo, mouse xenografts studies demonstrated that oral dosage, reduced tumor size significantly with reduction in proliferation marker Ki67 and these histone repressive marks. Finally conclude that inhibition of PRMT5 and EZH2 by EGCG potentially can be used to develop combined therapeutic approaches.

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“…As illustrated in Figure 1 , since the introduction of JQ1 by Mitsubishi in 2010 as the first efficient BRD4 inhibitor, both academic and industrial sectors have dedicated significant efforts to develop an array of BRD4 inhibitors for breast cancer treatment, with a particular focus on triple-negative breast cancer (TNBC) ( Gajjela and Zhou, 2023 ). Regrettably, no BRD4 inhibitors have yet cleared clinical trials to gain approval as cancer chemotherapy agents.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and evaluation of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one derivatives: potent BRD4 inhibitors with anti-breast cancer activity

Li,

Chu,

Yin

et al. 2023

Front. Pharmacol.

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BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 μM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 μM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.

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Bromodomain inhibitors and therapeutic applications

Cited by 25 publications

References 138 publications

mRNA display in cell lysates enables identification of cyclic peptides targeting the BRD3 extraterminal domain

mRNA display in cell lysates enables identification of cyclic peptides targeting the BRD3 extraterminal domain

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Design, synthesis, and evaluation of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one derivatives: potent BRD4 inhibitors with anti-breast cancer activity

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