Field-based rational design of p300 histone acetyltransferase inhibitor and systematic evaluation as an anti-fibrotic agent

Hwang, Soo Yeon; Park, Soo Yeon; Hong, Jung Yeon; Lee, Soo Yeon; Shin, Jae Ho; Na, Younghwa; Sohn, Myung Hyun; Yoon, Ho Geun; Kwon, Young Joo

doi:10.1039/d0cc03553j

Cited by 9 publications

(9 citation statements)

References 20 publications

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“…49 Alternatively, it can regulate histone acetylation directly, modifying the accessibility of promotor regions to transcription factors. 50 In the current experiments, an increase in H3KAc and H4KAC in the promoter of CCN2 tracked with the concomitant induction of this gene, whereas a reduction in the acetylation levels of these histones in the MMP9 gene promoter tracked with a reduction in the levels of expression of this transcript. The clinical significance of these results stands alone because they are an indication of the possibility of using histone acetyltransferase inhibitors to treat fibrosis.…”

Section: Discussionsupporting

confidence: 48%

“…Although, to date, no histone deacetylase inhibitor has reached US Food and Drug Administration approval status, recent evidence provides proof for this concept by showing that a selective p300 inhibitor can ameliorate fibrosis in a bleomycininduced model. 50 Similarly, plumbagin, which was shown to be an inhibitor of p300, suppresses fibrosis in an idiopathic pulmonary fibrosis model. 51 However, these data do not support a role of steroids, specifically triamcinolone, in counterregulating the effects of TGF-b1 by impacting the histone epigenome.…”

Section: Discussionmentioning

confidence: 99%

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Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Treviño-Villarreal

Reynolds

Langston

et al. 2021

The American Journal of Pathology

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Idiopathic subglottic stenosis (iSGS) is a progressive fibrotic disease characterized by life-threatening airway narrowing. Although the molecular underpinnings are unknown, previous reports showing that subglottic serial intralesional steroid injections (SILSIs) improve clinical outcomes suggest a steroidsensitive pathway in iSGS. Herein, a prospective study was conducted to determine the changes in profibrotic markers during SILSI to identify steroid-sensitive profibrotic drivers. Seven newly diagnosed patients with iSGS were recruited for SILSI. Subglottic biopsies before and after SILSI treatments were evaluated for histologic and molecular markers by confocal microscopy and RT-qPCR. At baseline, iSGS subglottises contained abundant vimentin-positive/a-smooth muscle actinenegative fibroblasts, intermingled with a matrix of fibronectin and types I and VI collagen. Transforming growth factor (TGF)-b1 was up-regulated primarily in glandular epithelium. Cellular communication network factor 2 (CCN2) was mainly up-regulated in stromal fibroblasts surrounding TGF-b1epositive glandular structures. SILSI improved iSGS by reducing fibroblast infiltration and increasing matrix remodeling. Mechanistically, SILSI counteracted the effects of TGF-b1 by inducing matrix metalloprotease 9 (MMP9) expression while repressing CCN2 expression, without affecting TGFb1 levels. Treatment of primary iSGS-derived fibroblasts with TGF-b1 recapitulated aspects of the disease in vivo, demonstrating that the induction in CCN2 and repression of MMP9 are caused by changes in histone acetylation induced by TGF-b1. Triamcinolone counteracted the coregulation of these genes by impairing SMAD2/3 binding to promoter regions, and not through histone acetylation. In conclusion, this study shows that SILSI counteracts a dysregulated TGF-b1/CCN2/MMP9 axis involved in iSGS development.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Treviño-Villarreal

Reynolds

Langston

et al. 2021

The American Journal of Pathology

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“…We previously reported that binding to acetyl-CoA, a p300 substrate, was comparable between A6 and a conventional p300 inhibitor, C646 ( 26 ). Furthermore, A6 demonstrated anti-fibrotic activity in TGF-β1-stimulated lung fibroblasts and in bleomycin-induced murine lung fibrosis in vivo .…”

Section: Resultsmentioning

confidence: 98%

Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis

Kim

Park

Lee

et al. 2023

BMB Rep

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Liver fibrosis is caused by chronic liver damage and results in the aberrant accumulation of extracellular matrix during disease progression. Despite the identification of the HAT enzyme p300 as a major factor for liver fibrosis, the development of therapeutic agents targeting the regulation of p300 has not been reported. We validated a novel p300 inhibitor (A6) on the improvement of liver fibrosis using two mouse models, mice on a choline-deficient high-fat diet and thioacetamide-treated mice. We demonstrated that pathological hall-marks of liver fibrosis were significantly diminished by A6 treatment through Masson's trichrome and Sirius red staining on liver tissue and found that A6 treatment reduced the expression of matricellular protein genes. We further showed that A6 treatment improved liver fibrosis by reducing the stability of p300 protein via disruption of p300 binding to AKT. Our findings suggest that targeting p300 through the specific inhibitor A6 has potential as a major therapeutic avenue for treating liver fibrosis. BMB Rep.

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“…Because of the significant inhibitory potency, they performed a preliminary characterization of this chalcone derivative as an anti-fibrotic agent in both TGF-β1-stimulated lung fibroblasts and bleomycin-induced in vivo lung fibrosis mice. Delightfully, based on the obtained findings, the chalcone derivative should represent a good starting point for developing anti-fibrotic drugs ( Hwang et al, 2020 ).…”

Section: Biocatalysismentioning

confidence: 99%

The green chemistry of chalcones: Valuable sources of privileged core structures for drug discovery

Marotta

Rossi²,

Ibba³

et al. 2022

Front. Chem.

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The sustainable use of resources is essential in all production areas, including pharmaceuticals. However, the aspect of sustainability needs to be taken into consideration not only in the production phase, but during the whole medicinal chemistry drug discovery trajectory. The continuous progress in the fields of green chemistry and the use of artificial intelligence are contributing to the speed and effectiveness of a more sustainable drug discovery pipeline. In this light, here we review the most recent sustainable and green synthetic approaches used for the preparation and derivatization of chalcones, an important class of privileged structures and building blocks used for the preparation of new biologically active compounds with a broad spectrum of potential therapeutic applications. The literature here reported has been retrieved from the SciFinder database using the term “chalcone” as a keyword and filtering the results applying the concept: “green chemistry”, and from the Reaxys database using the keywords “chalcone” and “green”. For both databases the time-frame was 2017–2022. References were manually selected based on relevance.

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Field-based rational design of p300 histone acetyltransferase inhibitor and systematic evaluation as an anti-fibrotic agent

Abstract: (E)-3-(3-(4-((3-Carbamoylbenzyl)oxy)-3-iodo-5-methoxyphenyl) acryloyl)benzamide (A6) was found as a potent p300 inhibitor (IC50 = 870 nM) showing a similar binding mode to that of acetyl-CoA, a p300 substrate and effective anti-fibrotic activity...

Cited by 9 publications

References 20 publications

Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis

The green chemistry of chalcones: Valuable sources of privileged core structures for drug discovery

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