Methyltransferase inhibitors for modulation of the epigenome and beyond

Schapira, Matthieu; Arrowsmith, C.H.

doi:10.1016/j.cbpa.2016.05.030

Cited by 27 publications

(18 citation statements)

References 48 publications

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“…For example, PKMT inhibitors, such as BIX-01294, UNC0638, UNC0642 (G9a/GLP), EPZ005687, GSK126, EI1, UNC1999, EPZ-6438, CPI-1205 (EZH2/EZH1), EPZ004777, SGC0946, EPZ-5676 (DOT1L), AZ-505 and LLY507 (SMYD2) are valuable chemical tools for further understanding biological functions of the targeted enzymes and have already been widely used in evaluating the therapeutic potential of these proteins (Table 1). [9,10] In addition, highly potent, selective, substrate-competitive PRMT inhibitors including MS023 (type I PRMTs), TP-064 (CARM1), EPZ015666 (PRMT5) and EPZ020411 (PRMT6) have been accomplished, suggesting that the substrate-binding grooves of PRMTs can also be successfully targeted (Table 1). [9,12,13] The discovery of the first allosteric PRMT3 inhibitor and the development of the PRMT3 chemical probe SGC707 have demonstrated that the allosteric binding site of PRMT3 can be exploited to yield potent, selective, and cell-active inhibitors, opening the door for discovering allosteric inhibitors of other PRMTs (Table 1).…”

Section: Recent Progress In Discovery Of Inhibitors Of Pmtsmentioning

confidence: 99%

“…[16–19] The design, synthesis and biological studies of many of these aforementioned inhibitors have already been discussed in detail in literature. [9,10] The following sections will focus only on the potent, selective small-molecule PMT inhibitors that are discovered very recently (indicated in bold type in Table 1). …”

Section: Recent Progress In Discovery Of Inhibitors Of Pmtsmentioning

confidence: 99%

“…[30] Small molecule inhibitors of SMYD2; AZ-505, A-893 and LLY-507 have already been reported and previously reviewed. [9,10] Very recently, in 2016, a screening campaign and optimization studies yielded in the discovery of enantiomerically pure ( S )-BAY-598 (Figure 2) as a cell- and in vivo -active inhibitor of SMYD2. [32] ( S )-BAY-598 shows >10-fold selectivity for SMYD2 over SMYD3 and >100-fold selectivity over 31 other methyltransferases.…”

Section: Inhibitors Of H3k4 and H3k36 Methyltransferasesmentioning

confidence: 99%

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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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Section: Recent Progress In Discovery Of Inhibitors Of Pmtsmentioning

confidence: 99%

Section: Recent Progress In Discovery Of Inhibitors Of Pmtsmentioning

confidence: 99%

Section: Inhibitors Of H3k4 and H3k36 Methyltransferasesmentioning

confidence: 99%

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Recent progress in developing selective inhibitors of protein methyltransferases

Kaniskan

Jin

2017

Current Opinion in Chemical Biology

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“…Methylation of Lysine as a biological hallmark has taken place in a conserved domain of SET (Suppressor of variegation, Enhancer of Zesta trithorax), which is composed of ~130 amino acid residues. EZH2 has two distant druggable sites on the surface of the SET-domain for binding of methyl donating cofactor, S-adenosyl methionine (SAM), and methyl-accepting substrate, H3K27me0 peptide respectively [3]. The substrate-binding site is structurally diverse since different substrates have been recognized by different histone methyltransferase (HMTase).…”

Section: Introductionmentioning

confidence: 99%

Structural dynamics of non-synonymous SNPs of histone methyltransferase EZH2 involved in Weaver Syndrome

Babu

Keshri

et al. 2020

Preprint

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Enhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 methyltransferases.Non-synonymous SNPs (nsSNPs) in the ezh2 gene may cause Weaver Syndrome that is a prominent and rare congenital disorder. Several EZH2 genetic variants have been characterized and reported, but there is no information available on their structural dynamics. Our study employs an in silico approach for structural and functional characterization of EZH2 nsSNPs. We identified 19 EZH2 nsSNPs majorly associated with Weaver Syndrome, among which four SET-domain nsSNPs including V621M, A677T, R679C, and H689Y significantly affected EZH2 structure. We conducted the triplicate of 100 ns of molecular dynamics simulations (MDS) to compare the dynamic interaction behaviors between wild-type and mutants of EZH2 with their substrate, H3K27me0 peptide. The simulation results revealed that the mutants had higher levels of structural variations as evidenced by secondary structure, density, distance plots, and principal component analysis. Compared to EZH2-WT, the mutants A677T and H689Y have shown lower binding energy with H3K27me0 peptide due to the denaturing of 310 helixes as exemplified by MM/PBSA calculations and secondary structure analysis. Our analysis shed light on mechanisms of structural variations of EZH2 nsSNPs and lay a stone to develop mutant-based therapeutic strategies for the design of target-specific scaffolds against Weaver Syndrome.

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“…17 Indeed, in addition to the clinical success of DNMT (DNA methyltransferase) inhibitors for treating cancer, 18 inhibitors targeting additional MTs like DOTL1 and EZH2 are under active clinical investigation. 19,20 …”

Section: Introductionmentioning

confidence: 99%

Chemical Proteomic Profiling of Human Methyltransferases

et al. 2016

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Methylation is a fundamental mechanism used in Nature to modify the structure and function of biomolecules, including proteins, DNA, RNA, and metabolites. Methyl groups are predominantly installed into biomolecules by a large and diverse class of S-adenosyl methionine (SAM)-dependent methyltransferases (MTs), of which there are ~200 known or putative members in the human proteome. Deregulated MT activity contributes to numerous diseases, including cancer, and several MT inhibitors are in clinical development. Nonetheless, a large fraction of the human MT family remains poorly characterized, underscoring the need for new technologies to characterize MTs and their inhibitors in native biological systems. Here, we describe a suite of S-adenosyl homocysteine (SAH) photoreactive probes and their application in chemical proteomic experiments to profile and enrich a large number of MTs (> 50) from human cancer cell lysates with remarkable specificity over other classes of proteins. We further demonstrate that the SAH probes can enrich MT-associated proteins and be used to screen for and assess the selectivity of MT inhibitors, leading to the discovery of a covalent inhibitor of nicotinamide N-methyltransferase (NNMT), an enzyme implicated in cancer and metabolic disorders. The chemical proteomics probes and methods for their utilization reported herein should prove of value for the functional characterization of MTs, MT complexes, and MT inhibitors in mammalian biology and disease.

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Methyltransferase inhibitors for modulation of the epigenome and beyond

Cited by 27 publications

References 48 publications

Recent progress in developing selective inhibitors of protein methyltransferases

Recent progress in developing selective inhibitors of protein methyltransferases

Structural dynamics of non-synonymous SNPs of histone methyltransferase EZH2 involved in Weaver Syndrome

Chemical Proteomic Profiling of Human Methyltransferases

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