ZLD1122, a novel EZH2 and EZH1 small molecular inhibitor, blocks H3K27 methylation and diffuse large B cell lymphoma cell growth

Gao, Tiantao; Zhang, Lidan; Zhu, Yiping; Song, Xian‐Rong; Feng, Qiang; Lei, Qian; Shi, Suxia; Deng, Hongxia; Xiong, Menghua; You, Xinyu; Zuo, Weiqiong; Liu, Li; Cheng, Peng; Wang, Ningyu; Ye, Tinghong; Xia, Yong; Yu, Luoting

doi:10.1039/c6ra00618c

Cited by 11 publications

(10 citation statements)

References 29 publications

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“…Shortly after the publication of ZLD1039, the same group reported ZLD1122, another potent and selective inhibitor of EZH2 and EZH1, which is structurally similar to ZLD1039. 137 ZLD1122 significantly reduced the H3K27me3 mark without affecting H3K9me3 and H3K4me3 marks in cell-based assays. It induced G0/G1 phase arrest in DLBCL cells and inhibited DLBCL cell growth.…”

Section: Protein Methyltransferasesmentioning

confidence: 90%

“…Oral dosing of ZLD1039 was well-tolerated, inhibited cell cycle-associated proteins and cell proliferation, and induced apoptosis. Shortly after the publication of ZLD1039, the same group reported ZLD1122, another potent and selective inhibitor of EZH2 and EZH1, which is structurally similar to ZLD1039 . ZLD1122 significantly reduced the H3K27me3 mark without affecting H3K9me3 and H3K4me3 marks in cell-based assays.…”

Section: Protein Methyltransferasesmentioning

confidence: 99%

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Inhibitors of Protein Methyltransferases and Demethylases

2017

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Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

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Section: Protein Methyltransferasesmentioning

confidence: 90%

Section: Protein Methyltransferasesmentioning

confidence: 99%

Inhibitors of Protein Methyltransferases and Demethylases

2017

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“…46 Again, on the basis of 6 , ZLD1039 ( 10 ), which is 12-fold selective for EZH2 over EZH1, has been discovered. 47,48 Most recently, compound 11 , a potent EZH2 inhibitor, was cocrystallized with the active Ac /human PRC2 complex. 14 …”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors

Yang

Konze

et al. 2016

J. Med. Chem.

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EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure-activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.

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“…Western blotting analysis was performed as described previously [24]. Briefly, cells were incubated separately with DMSO (vehicle control) or indicated concentration of YLT-LL-11 for 4 days.…”

Section: Methodsmentioning

confidence: 99%

A novel benzoxazinone derivative YLT-LL-11 inhibits diffuse large B-cell lymphoma growth via inducing cell cycle arrest and apoptosis

et al. 2019

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Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive B-cell non-Hodgkin’s lymphoma (NHL) with high treatment difficulty and high relapse rate. The bromodomain and extra-terminal (BET) proteins play significant roles in supporting the transcription of known DLBCL oncogene MYC, which provides a way for the development of targeted therapeutic agents to address this kind of malignant tumor. Here, we reported a novel benzoxazinone derivative YLT-LL-11 as potential BRD4 inhibitor and further investigated the biological activities against DLBCL. The results suggested that YLT-LL-11 inhibited cell growth against a panel of human hematopoietic malignancies cell lines in a dose- and time-dependent manner. In addition, flow cytometry and Western blotting assays showed that YLT-LL-11 inhibited the proliferation of a DLBCL cell line OCI-LY10 via inducing G0/G1 cell cycle arrest with regulation of the cyclin-dependent kinases (CDKs) expression. Furthermore, YLT-LL-11 facilitated OCI-LY10 cell apoptosis by up-regulation of pro-apoptotic protein BAX and down-regulation of anti-apoptotic protein Bcl-2. Taken together, these results revealed that BRD4 inhibitor YLT-LL-11 can down-regulate growth-associated transcription factors MYC in DLBCL thus resulted in cell growth inhibition and apoptosis.

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ZLD1122, a novel EZH2 and EZH1 small molecular inhibitor, blocks H3K27 methylation and diffuse large B cell lymphoma cell growth

Abstract: Here, we reported a novel, selective, small-molecule inhibitor of EZH2 and EZH1 synthesized by us, ZLD1122, which inhibited both EZH1 and wild type and mutant EZH2 activities with nanomolar potency.

Cited by 11 publications

References 29 publications

Inhibitors of Protein Methyltransferases and Demethylases

Inhibitors of Protein Methyltransferases and Demethylases

Structure–Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors

A novel benzoxazinone derivative YLT-LL-11 inhibits diffuse large B-cell lymphoma growth via inducing cell cycle arrest and apoptosis

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