LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2

Nguyen, Hannah; Allali-Hassani, Abdellah; Antonysamy, Stephen; Chang, Shawn S.; Chen, Lisa Hong; Curtis, Carmen; Emtage, Spencer; Fan, Li; Gheyi, T.; Li, Fengling; Liu, Shichong; Martin, Joseph R.; Mendel, David; Olsen, Jonathan B.; Pelletier, Laura; Shatseva, Tatiana; Wu, Song; Zhang, Feiyu Fred; Arrowsmith, C.H.; Brown, Peter J.; Campbell, Robert M.; Garcia, Benjamin A.; Baršytė-Lovejoy, Dalia; Mader, Mary M.; Vedadi, Masoud

doi:10.1074/jbc.m114.626861

Cited by 106 publications

(113 citation statements)

References 34 publications

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“…One group of targets is epigenetic enzymes that are highly up-regulated in cancers. In this regard, SMYD2 and PR-Set7 both are of therapeutic interest (30,31), in part because of their roles in p53 modifications (6,7,32). Our results add further importance to SMYD2 and PR-Set7 inhibitors as potential anticancer drug targets.…”

Section: Discussionmentioning

confidence: 52%

Lysine methylation represses p53 activity in teratocarcinoma cancer cells

Zhu

Dou

Sammons

et al. 2016

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

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TP53 (which encodes the p53 protein) is the most frequently mutated gene among all human cancers, whereas tumors that retain the wild-type TP53 gene often use alternative mechanisms to repress the p53 tumor-suppressive function. Testicular teratocarcinoma cells rarely contain mutations in TP53, yet the transcriptional activity of wild-type p53 is compromised, despite its high expression level. Here we report that in the teratocarcinoma cell line NTera2, p53 is subject to lysine methylation at its carboxyl terminus, which has been shown to repress p53's transcriptional activity. We show that reduction of the cognate methyltransferases reactivates p53 and promotes differentiation of the NTera2 cells. Furthermore, reconstitution of methylation-deficient p53 mutants into p53-depleted NTera2 cells results in elevated expression of p53 downstream targets and precocious loss of pluripotent gene expression compared with re-expression of wild-type p53. Our results provide evidence that lysine methylation of endogenous wild-type p53 represses its activity in cancer cells and suggest new therapeutic possibilities of targeting testicular teratocarcinoma.

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Section: Discussionmentioning

confidence: 52%

Lysine methylation represses p53 activity in teratocarcinoma cancer cells

Zhu

Dou

Sammons

et al. 2016

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

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“…Evidence thus suggests that SMYD2 is involved in cancer via transcriptional activation and inhibition, Rb-or p53-dependent cell-cycle control, and apoptosis. However, the lack of a driver role for p53 in SMYD2-mediated ESCC cell proliferation suggests that the mechanisms by which SMYD2 drives tumor cell proliferation may involve more than one substrate and may differ depending on cell type (18,34). To date, how SMYD2 specifically recognizes its substrates remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease

Li¹,

Fan²,

Zhou³

et al. 2017

Journal of Clinical Investigation

119

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Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 doubleknockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early-and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.

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“…According to literature, the binding interface of TP53 and SMYD2 is located between the catalytic SET domain (residue 1-282) and the C-terminal domain (47). In addition, SMYD2 has been reported to map primarily to the cytoplasm indicating SMYD2 targets a small subset of histones at specific chromatin loci as well as non-histone substrates (48).…”

Section: Resultsmentioning

confidence: 99%

From Single Variants to Protein Cascades

Mueller

Sommer

Backes

et al. 2016

Journal of Biological Chemistry

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Understanding the role of genetics in disease has become a central part of medical research. Non-synonymous single nucleotide variants (nsSNVs) in coding regions of human genes frequently lead to pathological phenotypes. Beyond single variations, the individual combination of nsSNVs may add to pathogenic processes. We developed a multiscale pipeline to systematically analyze the existence of quantitative effects of multiple nsSNVs and gene combinations in single individuals on pathogenicity. Based on this pipeline, we detected in a data set of 842 nsSNVs discovered in 76 genes related to cardiomyopathies, associated nsSNV combinations in seven genes present in at least 70% of all 639 patient samples, but not in a control cohort of healthy humans. Structural analyses of these revealed primarily an influence on the protein stability. For amino acid substitutions located at the protein surface, we generally observed a proximity to putative binding pockets. To computationally analyze cumulative effects and their impact, pathogenicity methods are currently being developed. Our approach supports this process, as shown on the example of a cardiac phenotype but can be likewise applied to other diseases such as cancer.

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LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2

Cited by 106 publications

References 34 publications

Lysine methylation represses p53 activity in teratocarcinoma cancer cells

Lysine methylation represses p53 activity in teratocarcinoma cancer cells

Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease

From Single Variants to Protein Cascades

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