Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays

Chen, Shijie; Li, Linjuan; Chen, Yantao; Hu, Jiawei; Liu, Ying; Liu, Yu-Chih; Liu, Rongfeng; Zhang, Yuanyuan; Meng, Fanwang; Zhu, Kongkai; Lu, Junyan; Zheng, Mingyue; Chen, Kaixian; Zhang, Jin; Jiang, Hualiang; Yao, Zhiyi; Luo, Cheng

doi:10.1021/acs.jcim.5b00738

Cited by 29 publications

(27 citation statements)

References 52 publications

(101 reference statements)

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“…In addition, a recent report described the identification of another non-SAM scaffold with IC 50 values in the micromolar range for DOT1L by virtual screening. 286 …”

Section: Protein Methyltransferasesmentioning

confidence: 99%

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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“…In addition, a recent report described the identification of another non-SAM scaffold with IC 50 values in the micromolar range for DOT1L by virtual screening. 286 …”

Section: Protein Methyltransferasesmentioning

confidence: 99%

Inhibitors of Protein Methyltransferases and Demethylases

2017

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“…These studies and several others 27, 28 demonstrate that molecular docking simulations can provide rapid screening of large compound libraries. However, these studies are most effective when the structure of the drug and the target be known a priori .…”

Section: Structure-based Drug Designmentioning

confidence: 66%

In silicoframeworks for systematic pre-clinical screening of potential anti-leukemia therapeutics

Ung

Varn

Cheng

2016

Expert Opinion on Drug Discovery

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Introduction Leukemia is a collection of highly heterogeneous cancers that arise from neoplastic transformation and clonal expansion of immature hematopoietic cells. Post-treatment recurrence is high, especially among elderly patients, thus necessitating more effective treatment modalities. Development of novel anti-leukemic compounds relies heavily on traditional in vitro screens which require extensive resources and time. Therefore, integration of in silico screens prior to experimental validation can improve the efficiency of pre-clinical drug development. Areas covered This article reviews different methods and frameworks used to computationally screen for anti-leukemic agents. In particular, three approaches are discussed including molecular docking, transcriptomic integration, and network analysis. Expert opinion Today’s data deluge presents novel opportunities to develop computational tools and pipelines to screen for likely therapeutic candidates in the treatment of leukemia. Formal integration of these methodologies can accelerate and improve the efficiency of modern day anti-leukemic drug discovery and ease the economic and healthcare burden associated with it.

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“…By genetic screening, the authors determined which enzymes overexpressed in cells induced disruption of telomeric silencing. These studies led to the isolation of several genes, some of which had not yet been identified, including DOT1, DOT4, DOT5, DOT6, and TLC1 [38]. Homolog genes of DOT1 (DOT1like or DOT1L) showed 88% similarity at amino acid level [39,40] and were subsequently found in mammals [41], Drosophila [42], and protozoa [43].…”

Section: Lysine Methyltransferases and Lysine Demethylasesmentioning

confidence: 99%

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

2019

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Methylation of histone 3 at lysine 79 (H3K79) is one of the principal mechanisms involved in gene expression. The histone methyltransferase DOT1L, which mono-, di-and trimethylates H3K79 using S-adenosyl-L-methionine as a co-factor, is involved in cell development, cell cycle progression, and DNA damage repair. However, changes in normal expression levels of this enzyme are found in prostate, breast, and ovarian cancer. High levels of H3K79me are also detected in acute myeloid leukaemia patients bearing MLL rearrangements (MLL-r). MLL translocations are found in approximately 80% of paediatric patients, leading to poor prognosis. DOT1L is recruited on DNA and induces hyperexpression of HOXA9 and MEIS1. Based on these findings, selective drugs have been developed to induce apoptosis in MLL-r leukaemia cells by specifically inhibiting DOT1L. The most potent DOT1L inhibitor pinometostat has been investigated in Phase I clinical trials for treatment of paediatric and adult patients with MLL-driven leukaemia, showing promising results. ARTICLE HISTORY

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Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays

Cited by 29 publications

References 52 publications

Inhibitors of Protein Methyltransferases and Demethylases

Inhibitors of Protein Methyltransferases and Demethylases

In silicoframeworks for systematic pre-clinical screening of potential anti-leukemia therapeutics

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

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