Anticancer Effects of I-BET151, an Inhibitor of Bromodomain and Extra-Terminal Domain Proteins

Lai, Jiacheng; Liu, Ziqiang; Zhao, Yulei; Ma, Chao; Huang, Haiyan

doi:10.3389/fonc.2021.716830

“…BETis are being investigated in clinical trials by increasing their stability and bioavailability, as well as by reducing their DLT. I-BET151, a novel dimethylisoxazole BETi, has been shown to induce G1 phase cell-cycle arrest and apoptosis in leukemic cells by downregulating BCL-2 [ 229 ]. I-BET151 is an I-BET762 analog with an increased in vivo half-life [ 219 ].…”

Section: Therapeutic Targeting Of Histone Modificationsmentioning

confidence: 99%

RETRACTED: Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies

Markouli¹,

Strepkos²,

Piperi³

2022

IJMS

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Hematologic malignancies are a large and heterogeneous group of neoplasms characterized by complex pathogenetic mechanisms. The abnormal regulation of epigenetic mechanisms and specifically, histone modifications, has been demonstrated to play a central role in hematological cancer pathogenesis and progression. A variety of epigenetic enzymes that affect the state of histones have been detected as deregulated, being either over- or underexpressed, which induces changes in chromatin compaction and, subsequently, affects gene expression. Recent advances in the field of epigenetics have revealed novel therapeutic targets, with many epigenetic drugs being investigated in clinical trials. The present review focuses on the biological impact of histone modifications in the pathogenesis of hematologic malignancies, describing a wide range of therapeutic agents that have been discovered to target these alterations and are currently under investigation in clinical trials.

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“…In cancer cells BRD4 bound Jagged-1 and NOTCH1 promoters, increasing the expression of both components and, thus, NOTCH pathway activation, which promotes proliferation and migration in tumors. In addition, I-BET151 impedes BRD4 binding to the NOTCH1 promoter, diminishing the expression of Hes1 and cancer-cell renewal activity [50,51]. Accordingly, we observed that JQ-1 downregulated Hes-1 and Hey-1 expression in NTS mice.…”

Section: Discussionmentioning

confidence: 53%

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

Tejedor-Santamaría¹,

Morgado‐Pascual²,

Márquez‐Expósito³

et al. 2021

Preprint

0

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Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treat-ment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provided limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory conditions and experi-mental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model of human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, including podocyte loss. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by targeting NOTCH signaling pathway. JQ1 inhibited the gene expression of the NOTCH effec-tors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

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“…In cancer cells BRD4 bound Jagged-1 and NOTCH1 promoters, increasing the expression of both components and, thus, NOTCH pathway activation, which promotes proliferation and migration in tumors. In addition, I-BET151 impedes BRD4 binding to the NOTCH1 promoter, diminishing the expression of Hes1 and cancer-cell renewal activity [66,67]. Accordingly, we observed that JQ-1 downregulated Hes-1 and Hey-1 expression in NTS mice.…”

Section: Discussionmentioning

confidence: 53%

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

Tejedor-Santamaría¹,

Morgado‐Pascual²,

Márquez‐Expósito³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treat-ment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provided limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory conditions and experi-mental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model of human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, including podocyte loss. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by targeting NOTCH signaling pathway. JQ1 inhibited the gene expression of the NOTCH effec-tors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

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Anticancer Effects of I-BET151, an Inhibitor of Bromodomain and Extra-Terminal Domain Proteins

Cited by 10 publications

References 107 publications

RETRACTED: Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies

RETRACTED: Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

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