A5103131022- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Chromatin Remodeling and Cancer
- Protein Degradation and Inhibitors
- Acute Myeloid Leukemia Research
- Photosynthetic Processes and Mechanisms
- Histone Deacetylase Inhibitors Research
- Photoreceptor and optogenetics research
- Hemoglobin structure and function
- Microbial Metabolic Engineering and Bioproduction
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Protein Structure and Dynamics
- Cancer Mechanisms and Therapy
- Biochemical and Molecular Research
- Mass Spectrometry Techniques and Applications
- Enzyme Catalysis and Immobilization
- Melanoma and MAPK Pathways
- Click Chemistry and Applications
- Pharmacogenetics and Drug Metabolism
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- Acute Lymphoblastic Leukemia research
- Neonatal Health and Biochemistry
Sheffield Hallam University
2021
Epizyme (United States)
2010-2019
Accent Therapeutics (United States)
2013-2018
Google (United States)
2018
CDI Laboratories (United States)
2015
Eisai (Japan)
2014
University of California, San Francisco
2010
GlaxoSmithKline (United States)
2006-2008
South College
2008
Johns Hopkins University
2006
Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid tumors. This alteration hypothesized to confer oncogenic dependency on EZH2 these cancers. We report discovery a potent, selective, and orally bioavailable small-molecule inhibitor enzymatic activity,...
EZH2, the catalytic subunit of PRC2 complex, catalyzes mono- through trimethylation lysine 27 on histone H3 (H3K27). Histone H3K27 is a mechanism for suppressing transcription specific genes that are proximal to site modification. Point mutations EZH2 gene (Tyr641) have been reported be linked subsets human B-cell lymphoma. The mutant allele always found associated with wild-type (heterozygous) in disease cells, and were ablate enzymatic activity complex methylating an unmodified peptide...
Mutations within the catalytic domain of histone methyltransferase EZH2 have been identified in subsets patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on enzymatic activity these cancers. We previously reported discovery EPZ005678 and EPZ-6438, potent selective S-adenosyl-methionine-competitive small molecule inhibitors EZH2. Although both compounds similar respect their mechanism action selectivity, EPZ-6438 possesses...
A survey of the human genome was performed to understand constituency protein methyltransferases (both arginine and lysine methyltransferases) relatedness their catalytic domains. We identified 51 methyltransferase proteins based on similarity canonical Drosophila Su(var)3-9, enhancer zeste (E(z)), trithorax (trx) domain. Disruptor telomeric silencing-1-like, a known methyltransferase, did not fit within family, but group with methyltransferases, along 44 other proteins, including METTL...
The SWI/SNF complex is a major regulator of gene expression and increasingly thought to play an important role in human cancer, as evidenced by the high frequency subunit mutations across virtually all cancer types. We previously reported that preclinical models, malignant rhabdoid tumors, which are deficient core component INI1 (SMARCB1), selectively killed inhibitors H3K27 histone methyltransferase EZH2. Given demonstrated antagonistic activities EZH2-containing PRC2 complex, we...
Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation histone can lead to oncogenic transformation. Enhancer Zeste homologue 2 (EZH2) methylates 3 at lysine 27 (H3K27) and abnormal this site is found many cancers. Tazemetostat, an EHZ2 inhibitor clinical development, has shown activity both preclinical models cancer as well patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure-activity relationships from...
DOT1L is the human protein methyltransferase responsible for catalyzing methylation of histone H3 on lysine 79 (H3K79). The ectopic activity DOT1L, associated with chromosomal translocation that a universal hallmark MLL ‐rearranged leukemia, required driver leukemogenesis in this malignancy. Here, we present studies structure–activity relationship aminonucleoside‐based inhibitors. Within series, find improvements target enzyme affinity and selectivity are driven entirely by diminution...
Heterozygous point mutations at Y641 and A677 in the EZH2 SET domain are prevalent about 10–24% of Non‐Hodgkin lymphomas (NHL). Previous studies indicate that these gain‐of‐function leading to hypertrimethylation H3K27. These may drive proliferation lymphoma make a molecular target for patients harboring mutations. Here, another mutation, A687V, occurring 1–2% patients, is also shown be mutation greatly enhances its ability perform dimethylation relative wild‐type equally proficient...
The recent publication of a potent and selective inhibitor protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe underlying pharmacology this key enzyme. Herein, we report design optimization strategies employed on an initial hit poor vitro clearance yield vivo additional molecule EPZ015866 (GSK3203591).
A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis analogues within this yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. overexpression reported in several cancer types suggesting that inhibition activity may have therapeutic utility. Identification EPZ020411 provides field with compound for target validation studies. shows good bioavailability following subcutaneous dosing rats making it a suitable vivo
Inhibitors of the protein methyltransferase Enhancer Zeste Homolog 2 (EZH2) may have significant therapeutic potential for treatment B cell lymphomas and other cancer indications. The ability scientific community to explore fully spectrum EZH2-associated pathobiology has been hampered by lack in vivo-active tool compounds this enzyme. Here we report discovery characterization EPZ011989, a potent, selective, orally bioavailable inhibitor EZH2 with useful pharmacokinetic properties. EPZ011989...
CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation RNA processing. overexpression has been reported multiple cancer types shown to modulate oncogenic pathways vitro studies. Detailed understanding mechanism action oncogenesis limited by a lack selective tool compounds, particularly for vivo We describe identification characterization of, our knowledge, first potent...
EPZ-5676 [(2<i>R</i>,3<i>R</i>,4<i>S</i>,5<i>R</i>)-2-(6-amino-9<i>H</i>-purin-9-yl)-5-((((1<i>r</i>,3<i>S</i>)-3-(2-(5-(<i>tert</i>-butyl)-1<i>H</i>-benzo[<i>d</i>]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing <i>MLL</i>-rearrangements (<i>MLL</i>-r). In this study, we evaluated in combination with standard care (SOC)...
ABSTRACT Retapamulin is a semisynthetic pleuromutilin derivative being developed as topical antibiotic for treating bacterial infections of the skin. It potent in vitro against susceptible and multidrug-resistant organisms commonly associated with skin infections. We report detailed mode action studies demonstrating that retapamulin binds to ribosome high affinity, inhibits ribosomal peptidyl transferase activity, partially binding initiator tRNA substrate P-site. Taken together, these data...