Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas

Vaswani, Rishi G.; Gehling, Victor S.; Dakin, Les A.; Cook, Andrew S.; Nasveschuk, Christopher G.; Duplessis, Martin; Iyer, Priyadarshini; Balasubramanian, Srividya; Zhao, Feng; Good, Andrew C.; Campbell, Robert M.; Lee, Christina; Cantone, Nico; Cummings, Richard; Normant, Emmanuel; Bellon, Steven F.; Albrecht, Brian K.; Harmange, Jean-Christophe; Trojer, Patrick; Audia, James E.; Zhang, Ying; Justin, Neil; Chen, Shuyang; Wilson, J.; Gamblin, Steven J.

doi:10.1021/acs.jmedchem.6b01315

Cited by 193 publications

(163 citation statements)

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“…Polycomb proteins comprise at least two different complexes, the Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) [36]. Polycomb repressive complex 2 (PRC2) plays a principal role in transcriptional silencing by placing methylation marks on lysine 27 of histone H3 [37,38]. Dysregulation of PRC2 function is associated with certain malignancies and poor prognosis [37,38].…”

Section: The Impact Of Melatonin On Tumor Stem Cells Melatonin Inhibimentioning

confidence: 99%

“…Polycomb repressive complex 2 (PRC2) plays a principal role in transcriptional silencing by placing methylation marks on lysine 27 of histone H3 [37,38]. Dysregulation of PRC2 function is associated with certain malignancies and poor prognosis [37,38]. Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of PRC2.…”

Section: The Impact Of Melatonin On Tumor Stem Cells Melatonin Inhibimentioning

confidence: 99%

“…Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of PRC2. Therefore, EZH2 is regarded as an essential target for pharmacological intervention [37,38]. EZH2 is involved in inhibiting gene expression through methylation of histone H3 on lysine 27.…”

Section: The Impact Of Melatonin On Tumor Stem Cells Melatonin Inhibimentioning

confidence: 99%

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The impact of melatonin and carbon ion irradiation on cancer stem cells

Liu¹,

Reíter²

2017

Nucl Med Biomed Imaging

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Aim: Cancer stem cells (CSCs) exhibited an excessive migratory and invasive potential. Melatonin may inhibit multiple crucial signals associated with tumor stem cell self-renewal, viability, invasiveness, tumor growth, and therapy resistance. Carbon ion irradiation may be a promising therapeutic modality in both non-stem-like and stem-like tumor cells in contrast to photon irradiation. A comprehensive understanding of the mechanisms and molecular pathways associated with invasive properties of CSCs is essential in developing novel treatment options for cancer therapy that target CSCs. Materials and methods:A systematic review of the existing literature was conducted using the following search terms: 'melatonin', 'X-ray irradiation', 'charged particle irradiation', 'carbon ion irradiation', 'cancer stem cells', 'tumor-initiating cells' and 'cancer stem-like cells'. The search used PubMed and spanned the period from January 2000 to December 2016. Conclusion:Cancer stem cells possess the capacity of self-renewal and pluripotency, generating all cells within a tumor, and are responsible for tumor growth, therapy resistance and metastasis. Melatonin attenuated AKT activation, EZH2 S21 phosphorylation, EZH2-STAT3 interactions and altered histone modifications to reduce tumor initiation and propagation of brain tumor stem cells (BTSC). Melatonin increases the efficacy of chemotherapeutic agents, targeting both the tumor bulk and BTSCs through the regulation of the expression and function of the ABCG2/BCRP transporter by inducing the methylation of its promoter. Melatonin treatment induced cell death with ultrastructural characteristics of autophagy. Breast cancer stem cells (BCSCs) are responsive to melatonin treatment by way of reducing the viability and the invasiveness of breast cancer mammospheres as well as regulating the expression of OCT4, N-cadherin and vimentin proteins associated with epithelial mesenchymal transition in BCSCs. Carbon irradiation is effective in brain tumor stem cell (BTSC) elimination with relative biologic effectiveness (RBE) in the range of 1.87-3.44. Carbon ion irradiation may be a promising therapeutic modality because it reduces migration and invasion processes in both head and neck squamous cell carcinoma and cancer stem cells in contrast to photon irradiation. Low LET X-ray irradiation may essentially eradicate the non-stem-like tumor cells, consequently the radioresistant cancer stem-like cell population is obviously enriched. In contrast, carbon ion irradiation may eradicate both non-stemlike and stem-like tumor cells at the same time. Carbon ion irradiation is a promising tool to eradicate putative colon cancer stem-like cells. Further investigation to elucidate the mechanisms and molecular pathways involved in cancer stem cells particularly associated with melatonin and carbon ion irradiation certainly is warranted.

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Section: The Impact Of Melatonin On Tumor Stem Cells Melatonin Inhibimentioning

confidence: 99%

Section: The Impact Of Melatonin On Tumor Stem Cells Melatonin Inhibimentioning

confidence: 99%

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The impact of melatonin and carbon ion irradiation on cancer stem cells

Liu¹,

Reíter²

2017

Nucl Med Biomed Imaging

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“…EZH2 inhibitors have been shown to be active against a wide range of human neoplasms, and some of these new drugs are being tested in clinical trials [39,40]. This emerging evidence reinforces the need for identifying reliable and non-invasive biomarkers to predict the expression and function of EZH2 in patients.…”

mentioning

confidence: 86%

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

et al. 2017

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Abstract:The enhancer of zeste homolog 2 (EZH2) gene encodes a histone methyltransferase that is a catalytic subunit of the Polycomb repressive complex 2 (PRC2) group of proteins that act to repress gene expression. The EZH2 locus is rarely mutated in solid tumors and there is no comprehensive study of EZH2 single nucleotide variants (SNVs) associated with cancer susceptibility, prognosis and response to therapy. Here, for the first time, we review the functional roles of EZH2 DNA variants and propose a putative etiological role in 10 various solid tumors including: esophageal, hepatocellular, oral, urothelial, colorectal, lung and gastric cancers. In particular, we found that the C allele of the EZH2 variant rs3757441 is associated with increased EZH2 RNA expression and poorer prognosis (advanced stage) in at least two malignancies such as colorectal and hepatocellular carcinoma. This suggests that the C allele may be a functional risk variant in multiple malignant tumors. We therefore propose that the rs3757441 single nucleotide variant (SNV) be genotyped and real-time PCR assays be performed in large cohort studies in order to confirm this preliminary finding that could be useful for clinical practice.

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“…[22] Recently the discovery of CPI-1205, displaying high potency, selectivity, and cellular activity was added to the list of pyridone containing inhibitors. [23] A co-crystal structure of an analog of CPI-1205 bound to human PRC2 was also obtained. [23] In addition, very recently, new series of pyridone containing inhibitors, which led to the discovery of highly potent EZH2 inhibitor 1 (Figure 2) was reported.…”

Section: Inhibitors Of H3k9 and H3k27 Methyltransferasesmentioning

confidence: 99%

Recent progress in developing selective inhibitors of protein methyltransferases

Kaniskan

Jin

2017

Current Opinion in Chemical Biology

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Mounting evidence suggests that protein methyltrans•ferases (PMTs), which catalyze methylation of histone as well as non-histone •proteins, play aa crucial role in diverse biological pathways and human• diseases. In particular, PMTs have been recognized as major players in •regulating gene expression and chromatin state. There has been an increasingly growing• interest in these enzymes as potential therapeutic targets and over the past two years tremendous progress has been made in the discovery of selective, small molecule inhibitors of protein lysine and arginine methyltransferases. Inhibitors of PMTs have been used extensively in oncology studies as tool compounds, and inhibitors of EZH2, DOT1L and PRMT5 are currently in clinical trials.

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Cited by 193 publications

References 31 publications

The impact of melatonin and carbon ion irradiation on cancer stem cells

The impact of melatonin and carbon ion irradiation on cancer stem cells

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

Recent progress in developing selective inhibitors of protein methyltransferases

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