Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294

Chang, Yanqi; Zhang, Xing; Horton, J.R.; Upadhyay, Anup K.; Spannhoff, Astrid; Liu, Jin; Snyder, James P.; Bedford, Mark T.; Cheng, Xiaodong

doi:10.1038/nsmb.1560

Cited by 282 publications

(318 citation statements)

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“…These results indicate that BIX-01294 does indeed exert an effect on parasite histone methylation levels, and this effect is not simply a consequence of parasites dying. Together with its significant precedence as an HKMT inhibitor (33)(34)(35)(36)(37)(38), this result is highly suggestive of inhibition of parasite histone methyltransferase activity.…”

Section: Resultsmentioning

confidence: 65%

“…BIX-01294 was shown to be noncompetitive for the methyl donor S-adenosylmethionine and instead competitive for the histone substrate (30,37). In light of the high precedence of this class of compounds to serve as mammalian HKMT inhibitors (33)(34)(35)(36)(37)(38), focused BIX-01294 derivatives were explored for the development of parasitespecific histone methyltransferase inhibitors in our study. Our discovery that BIX-01294-treated and TM2-115-treated P. falciparum parasites exhibit greatly reduced H3K4me3 levels in BIX-01294-treated parasites, while maintaining a distinct profile compared with human cell lines treated with BIX-01294, is highly supportive of our compounds acting as parasite histone methyltransferase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…S1) have resulted only in very low enzymatic activity. There is evidence that this small-molecule scaffold can be tuned to effect HKMT specificity (33)(34)(35)(36)(37)(38), in particular altering activity against HKMTs other than G9a. It is highly likely that focused medicinal chemistry efforts will enable further specificity of these compounds toward their parasite targets.…”

Section: Discussionmentioning

confidence: 99%

“…1) was discovered in a high-throughput screen and was shown to be an inhibitor of the HKMTs G9a/GLP (30). BIX-01294 has also been used successfully in stem cell modulation (31,32), and subsequent medicinal chemistry studies have shown the potential of this scaffold in the discovery of compounds with increased potency, selectivity, and cellular permeability (33)(34)(35)(36)(37)(38). In this work, we identified two compounds that target histone methylation in P. falciparum.…”

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confidence: 97%

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Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Malmquist

Moss

Mécheri

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

122

116

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Epigenetic factors such as histone methylation control the developmental progression of malaria parasites during the complex life cycle in the human host. We investigated Plasmodium falciparum histone lysine methyltransferases as a potential target class for the development of novel antimalarials. We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC 50 values of ∼100 nM, values at least 22-fold more potent than their apparent IC 50 toward two human cell lines and one mouse cell line. These compounds irreversibly arrested parasite growth at all stages of the intraerythrocytic life cycle. Decrease in parasite viability (>40%) was seen after a 3-h incubation with 1 µM BIX-01294 and resulted in complete parasite killing after a 12-h incubation. Additionally, mice with patent Plasmodium berghei ANKA strain infection treated with a single dose (40 mg/kg) of TM2-115 had 18-fold reduced parasitemia the following day. Importantly, treatment of P. falciparum parasites in culture with BIX-01294 or TM2-115 resulted in significant reductions in histone H3K4me3 levels in a concentration-dependent and exposure time-dependent manner. Together, these results suggest that BIX-01294 and TM2-115 inhibit malaria parasite histone methyltransferases, resulting in rapid and irreversible parasite death. Our data position histone lysine methyltransferases as a previously unrecognized target class, and BIX-01294 as a promising lead compound, in a presently unexploited avenue for antimalarial drug discovery targeting multiple life-cycle stages.chromatin | global health | chemical genetics M alaria continues to claim >1 million lives annually, particularly in the vulnerable populations of pregnant women and children <5 y of age (1, 2). Although artemisinin-based combination therapies have helped rescue the world's antimalarial armamentarium, the parasite's ability to develop resistance continues to outpace our ability to control this devastating disease (3). Effective malaria drug discovery efforts must therefore include both the development of improved antimalarials from existing compounds and the discovery of new parasite drug targets and novel small-molecule inhibitors.Epigenetic control of gene regulation in Plasmodium falciparum, the main causative agent of human malaria, has received considerable attention originally due to the apparent lack of recognizable transcription factors in the parasite genome (4). Although the recent discovery of a family of apicomplexan AP2 transcription factors (5, 6) has partly fulfilled the search for more traditional transcription factors, epigenetic gene regulation, particularly at the level of histone posttranslational modifications, has proven to play a significant role in P. falciparum virulence gene regulation. For example, expression of variant surface antigen gene families (7) and ligands involved in parasite red bl...

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Section: Resultsmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

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Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Malmquist

Moss

Mécheri

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

122

116

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“…G9a heterodimerises with G9a-like protein (GLP) via its carboxyl terminal SET domain to exert the full spectrum of its substrate methylation specificity 18,19 . Both proteins (independently and in the complex) catalyse mono-and dimethylation of lysine 9 and lysine 27 of H3 (H3K9 and H3K27, respectively) [20][21][22] and histone H1 isotype 4 (H1.4) (Trojer et al…”

Section: Introductionmentioning

confidence: 99%

Human EHMT2/G9a activates p53 through methylation-independent mechanism

et al. 2016

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ABSTRACTp53 is a critical tumor suppressor in humans. It functions mostly as a transcriptional factor and its activity is regulated by numerous post-translational modifications. Among different covalent modifications found on p53 the most controversial one is lysine methylation. We found that human G9a (hG9a) unlike its mouse orthologue (mG9a) potently stimulated p53 transcriptional activity. Both ectopic and endogenous hG9a augmented p53-dependent transcription of pro-apoptotic genes, including Bax and PUMA, resulting in enhanced apoptosis and reduced colony formation. Significantly, siRNA-mediated knockdown of hG9a attenuated p53-dependent activation of PUMA. On the molecular level, hG9a interacted with histone acetyltransferase, p300/CBP, resulting in increased histone acetylation at the promoter of PUMA. The bioinformatics data substantiated our findings showing that positive correlation between G9a and p53 expression is associated with better survival of lung cancer patients. Collectively, this study demonstrates that depending on the cellular and organismal context, orthologous proteins may exert both overlapping and opposing functions.Furthermore, this finding has important ramifications on the use of G9a inhibitors in combination with genotoxic drugs to treat p53-positive tumors.3

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Epigenetic Proteins as Emerging Drug Targets

Boriack-Sjodin

2020

Structural Biology in Drug Discovery

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Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294

Cited by 282 publications

References 36 publications

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Human EHMT2/G9a activates p53 through methylation-independent mechanism

Epigenetic Proteins as Emerging Drug Targets

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