Analogues of the Natural Product Sinefungin as Inhibitors of EHMT1 and EHMT2

Devkota, Kanchan; Lohse, Brian; Liu, Qing; Wang, Mingwei; Berthelsen, Jens; Clausen, Rasmus P.

doi:10.1021/ml4002503

Cited by 37 publications

(22 citation statements)

References 28 publications

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“…Sinefungin is an AdoMet analogue containing an aminomethylene group in place of the methylated sulfonium group that typically acts as the methyl donor. It competes with AdoMet for MTase-binding and thereby inhibits AdoMet-dependent MTases in a non-selective manner [ 35 , 36 ].…”

Section: Resultsmentioning

confidence: 99%

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

et al. 2018

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The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addition, there is emerging evidence for drug resistance. AN5568 (SCYX-7158) is a novel benzoxaborole class compound that has been selected as a lead compound for the treatment of HAT, and has demonstrated effective clearance of both early and late stage trypanosomiasis in vivo. The compound is currently awaiting phase III clinical trials and could lead to a novel oral therapeutic for the treatment of HAT. However, the mode of action of AN5568 in T. brucei is unknown. This study aimed to investigate the mode of action of AN5568 against T. brucei, using a combination of molecular and metabolomics-based approaches.Treatment of blood-stage trypanosomes with AN5568 led to significant perturbations in parasite metabolism. In particular, elevated levels of metabolites involved in the metabolism of S-adenosyl-L-methionine, an essential methyl group donor, were found. Further comparative metabolomic analyses using an S-adenosyl-L-methionine-dependent methyltransferase inhibitor, sinefungin, showed the presence of several striking metabolic phenotypes common to both treatments. Furthermore, several metabolic changes in AN5568 treated parasites resemble those invoked in cells treated with a strong reducing agent, dithiothreitol, suggesting redox imbalances could be involved in the killing mechanism.

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Section: Resultsmentioning

confidence: 99%

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

et al. 2018

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“…Currently known inhibitors of SET‐domain histone methyltransferases function as either competitive inhibitors of the substrate peptides or inhibitors of the cofactor AdoMet. For example, compounds such as BIX01294, E72, and UNC0321 have been found to block binding of the target peptide of H3 to the histone methyltransferase G9a, and Sinefungin derivatives have been developed that bind in place of AdoMet . Targeting histone methyltransferases via these mechanisms may be potentially difficult because of the need to develop specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…For example, compounds such as BIX01294, E72, and UNC0321 have been found to block binding of the target peptide of H3 to the histone methyltransferase G9a, and Sinefungin derivatives have been developed that bind in place of Ado-Met. 12,[20][21][22][23] Targeting histone methyltransferases via these mechanisms may be potentially difficult because of the need to develop specific inhibitors. Indeed, Nguyen et al have studied the binding site similarity of SET-domain methyltransferases and found scaffolds that may bind to subsets of these.…”

Section: Discussionmentioning

confidence: 99%

Dynamic behavior of the post‐SET loop region of NSD1: Implications for histone binding and drug development

2016

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NSD1 is a SET-domain histone methyltransferase that methylates lysine 36 of histone 3. In the crystal structure of NSD1, the post-SET loop is in an autoinhibitory position that blocks binding of the histone peptide as well as the entrance to the lysine-binding channel. The conformational dynamics preceding histone binding and the mechanism by which the post-SET loop moves to accommodate the target lysine is currently unknown, although potential models have been proposed. Using molecular dynamics simulations, we have identified potential conformations of the post-SET loop differing from those of previous studies, as well as proposed a model of peptidebound NSD1. Our simulations illustrate the dynamic behavior of the post-SET loop and the presence of a few distinct conformations. In every case, the post-SET loop remains in an autoinhibitory position blocking the peptide-binding cleft, suggesting that another interaction is required to optimally position NSD1 in an active conformation. This finding provides initial evidence for a mechanism by which NSD1 preferentially binds nucleosomal substrates.

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“…Moreover, although the conformation of bound SAM cofactor is very similar across different SET domains due to a precise hydrogen bond network, SAM-binding pockets contain enough structural diversity surrounding this network to allow development of specific inhibitors for different KMTases [135]. Indeed, chemical modification of SAM or closely related compounds such as sinefungin has led to potent and specific inhibitors for future science group Review Rogawski, Grembecka & Cierpicki several KMTases [122,136,137]. An additional consideration for designing SAM-derivative inhibitors is that the SAM-binding pocket is immediately adjacent to the narrow substrate lysine-binding channel.…”

Section: Post-setmentioning

confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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Analogues of the Natural Product Sinefungin as Inhibitors of EHMT1 and EHMT2

Cited by 37 publications

References 28 publications

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

Dynamic behavior of the post‐SET loop region of NSD1: Implications for histone binding and drug development

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

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