PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-8 (8)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
1.  The emerging role of lysine methyltransferase SETD8 in human diseases 
Clinical Epigenetics  2016;8:102.
SETD8/SET8/Pr-SET7/KMT5A is the only known lysine methyltransferase (KMT) that monomethylates lysine 20 of histone H4 (H4K20) in vivo. Lysine residues of non-histone proteins including proliferating cell nuclear antigen (PCNA) and p53 are also monomethylated. As a consequence, the methyltransferase activity of the enzyme is implicated in many essential cellular processes including DNA replication, DNA damage response, transcription modulation, and cell cycle regulation. This review aims to provide an overview of the roles of SETD8 in physiological and pathological pathways and to discuss the progress made to date in inhibiting the activity of SETD8 by small molecules, with an emphasis on their discovery, selectivity over other methyltransferases and cellular activity.
doi:10.1186/s13148-016-0268-4
PMCID: PMC5034662  PMID: 27688818
3.  Synthesis and Evaluation of Translocator 18 kDa Protein (TSPO) Positron Emission Tomography (PET) Radioligands with Low Binding Sensitivity to Human Single Nucleotide Polymorphism rs6971 
ACS Chemical Neuroscience  2014;5(10):963-971.
The imaging of translocator 18 kDa protein (TSPO) in living human brain with radioligands by positron emission tomography (PET) has become an important means for the study of neuroinflammatory conditions occurring in several neuropsychiatric disorders. The widely used prototypical PET radioligand [11C](R)-PK 11195 ([11C](R)-1; [N-methyl-11C](R)-N-sec-butyl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide) gives a low PET signal and is difficult to quantify, whereas later generation radioligands have binding sensitivity to a human single nucleotide polymorphism (SNP) rs6971, which imposes limitations on their utility for comparative quantitative PET studies of normal and diseased subjects. Recently, azaisosteres of 1 have been developed with improved drug-like properties, including enhanced TSPO affinity accompanied by moderated lipophilicity. Here we selected three of these new ligands (7–9) for labeling with carbon-11 and for evaluation in monkey as candidate PET radioligands for imaging brain TSPO. Each radioligand was readily prepared by 11C-methylation of an N-desmethyl precursor and was found to give a high proportion of TSPO-specific binding in monkey brain. One of these radioligands, [11C]7, the direct 4-azaisostere of 1, presents many radioligand properties that are superior to those reported for [11C]1, including higher affinity, lower lipophilicity, and stable quantifiable PET signal. Importantly, 7 was also found to show very low sensitivity to the human SNP rs6971 in vitro. Therefore, [11C]7 now warrants evaluation in human subjects with PET to assess its utility for imaging TSPO in human brain, irrespective of subject genotype.
doi:10.1021/cn500138n
PMCID: PMC4210126  PMID: 25123416
TSPO; PET; radioligand; carbon-11; imaging; brain
4.  A TR-FRET based functional assay for screening activators of CARM1 
Chembiochem : a European journal of chemical biology  2013;14(7):10.1002/cbic.201300029.
Epigenome is an emerging field that demands selective cell-permeable chemical probes to perturb, especially in vivo, the activity of specific enzymes involved in modulating the epigenetic codes. Coactivator Associated Arginine (R) Methyltransferase 1 (CARM1) is a coactivator of estrogen receptor α (ERα), the main target in human breast cancer. We previously showed that overexpression of CARM1 by two-fold in MCF7 breast cancer cells increased the expression of ERα-target genes involved in differentiation and reduced cell proliferation, leading to the hypothesis that activating CARM1 by chemical activators may be therapeutically effective in breast cancer. Selective, potent, cell-permeable CARM1 activators will be essential to test this hypothesis. Here we report the development of a cell-based, time-resolved Förster resonance energy transfer (TR-FRET) assay using poly (A) binding protein 1 (PABP1) methylation to monitor cellular activity of CARM1. The LanthaScreen® TR-FRET assay utilizes MCF7 cells expressing GFP-PABP1 fusion protein via BacMam gene delivery system, methyl-PABP1 specific antibody and terbium-labeled secondary antibody. This assay has been validated to reflect the expression and/or activity of CARM1 and optimized for high throughput screening to identify CARM1 allosteric activators. This TR-FRET platform serves as a generic tool for functional screening of cell-permeable, chemical modulators of CARM1 for elucidation of its in vivo functions.
doi:10.1002/cbic.201300029
PMCID: PMC3828750  PMID: 23585185
Arginine methylation; CARM1; PABP1; TR-FRET
5.  Identification of Small-Molecule Enhancers of Arginine Methylation Catalyzed by Coactivator-Associated Arginine Methyltransferase 1 
Journal of medicinal chemistry  2012;55(22):9875-9890.
Arginine methylation is a common post-translational modification that is crucial in modulating gene expression at multiple critical levels. The arginine methyltransferases (PRMTs) are envisaged as promising druggable targets but their role in physiological and pathological pathways is far from being clear, due to the limited number of modulators reported to date. In this effort, enzyme activators can be invaluable tools useful as gain-of-function reagents to interrogate the biological roles in cells and in vivo of PRMTs. Yet the identification of such molecules is rarely pursued. Herein we describe a series of aryl ureido acetamido indole carboxylates (dubbed “uracandolates”), able to increase the methylation of histone- (H3) or non-histone (polyadenylate-binding protein 1, PABP1) substrates induced by coactivator-associated arginine methyltransferase 1 (CARM1), both in in vitro and cellular settings. To the best of our knowledge, this is the first report of compounds acting as CARM1 activators.
doi:10.1021/jm301097p
PMCID: PMC3508294  PMID: 23095008
CARM1 activator; PRMT inhibitors; arginine methyltransferase; histone modifying enzyme; epigenetics
6.  Enhancement of lysine acetylation accelerates wound repair 
In physiopathological conditions, such as diabetes, wound healing is significantly compromised and chronic complications, including ulcers, may occur. In a mouse model of skin repair, we recently reported that wound treatment with Sirtuin activators and class I HDAC inhibitors induced keratinocyte proliferation and enhanced healing via a nitric oxide (NO) dependent mechanism. We observed an increase in total protein acetylation in the wound area, as determined by acetylation of α-tubulin and histone H3 Lysine 9. We reasoned that this process activated cell function as well as regulated gene expression to foster tissue repair. We report here that the direct activation of P300/CBP-associated factor (PCAF) by the histone acetylase activator pentadecylidenemalonate 1b (SPV-106) induced Lysine acetylation in the wound area. This intervention was sufficient to enhance repair process by a NO-independent mechanism. Hence, an impairment of PCAF and/or other GCN5 family acetylases may delay skin repair in physiopathological conditions.
doi:10.4161/cib.25466
PMCID: PMC3829946  PMID: 24265859
Lysine acetylation; epigenetics; PCAF; wound healing; nitric oxide; keratinocyte
7.  p300/CBP-associated factor selectively regulates the extinction of conditioned fear 
It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically-dependent memory, particularly when there is competition between opposing memory traces such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57/Bl6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional co-activator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.
doi:10.1523/JNEUROSCI.0178-12.2012
PMCID: PMC3466419  PMID: 22933779
PCAF; fear extinction; infralimbic prefrontal cortex; ATF4; zif268; memory; H3-CoA-20-Tat; SPV106
8.  Novel 3,5-Bis(bromohydroxybenzylidene)piperidin-4-ones as Coactivator-associated Arginine Methyltransferase 1 Inhibitors: Enzyme Selectivity and Cellular Activity 
Journal of medicinal chemistry  2011;54(13):4928-4932.
Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene) piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.
doi:10.1021/jm200453n
PMCID: PMC3487391  PMID: 21612300

Results 1-8 (8)