A5032612285- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Biochemical and Molecular Research
- Sirtuins and Resveratrol in Medicine
- Cytomegalovirus and herpesvirus research
- Protein Degradation and Inhibitors
- Parasitic Infections and Diagnostics
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- HER2/EGFR in Cancer Research
- Multiple Myeloma Research and Treatments
- Cancer Genomics and Diagnostics
- Biochemical effects in animals
- RNA modifications and cancer
- Neonatal Health and Biochemistry
- Neuroblastoma Research and Treatments
- Tea Polyphenols and Effects
- Herpesvirus Infections and Treatments
- Tuberculosis Research and Epidemiology
- Genomics and Chromatin Dynamics
- Histone Deacetylase Inhibitors Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Autophagy in Disease and Therapy
- Hemoglobin structure and function
- Infective Endocarditis Diagnosis and Management
Epizyme (United States)
2015-2022
Tris Pharma (United States)
2013-2015
GlaxoSmithKline (United States)
2015
Boston University
2008-2015
Brandeis University
2003-2011
Florida State University
2011
It's a SIRT Intense attention has focused on the SIRT1 deacetylase as possible target for anti-aging drugs. But unexpected complications in assays of activity have made it unclear whether compounds thought to be sirtuin-activating (STACs) are really direct regulators enzyme. Further exploration these effects by Hubbard et al. (p. 1216 ; see Perspective Yuan and Marmorstein ) revealed that interaction with certain substrates allows activation STACs identified critical amino acids required...
Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates NF-κB, activity which modulated by post-translational modifications as well association with co-activator and co-repressor proteins. SIRT1, an NAD(+)-dependent deacetylase, has been shown to suppress NF-κB signaling through deacetylation p65 subunit resulting reduction inflammatory responses mediated this transcription factor. The role SIRT1 regulation...
SIRT1 is a protein deacetylase that has emerged as therapeutic target for the development of activators to treat diseases aging. SIRT1-activating compounds (STACs) have been developed produce biological effects consistent with direct activation. At molecular level, mechanism by which STACs activate remains elusive. In studies reported herein, activation examined using representative chosen from collection STACs. These reveal strongly dependent on structural features peptide substrate....
SIRT1, the founding member of mammalian family seven NAD(+)-dependent sirtuins, is composed 747 amino acids forming a catalytic domain and extended N- C-terminal regions. We report design characterization an engineered human SIRT1 construct (mini-hSIRT1) containing minimal structural elements required for lysine deacetylation activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved crystal structure mini-hSIRT1-STAC complex, which revealed...
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
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...
SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have available for target validation studies. A novel oxindole series was identified through screening the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at level sufficient to probe vitro biology inhibition. shows good bioavailability following...
The protozoan parasite Cryptosporidium parvum causes severe enteritis with substantial morbidity and mortality among AIDS patients young children. No fully effective treatment is available. C. relies on inosine 5'-monophosphate dehydrogenase (IMPDH) to produce guanine nucleotides highly susceptible IMPDH inhibition. Furthermore, obtained its gene by lateral transfer from an epsilon-proteobacterium, suggesting that the enzyme might have very different characteristics than human counterpart....
A key challenge in the development of precision medicine is defining phenotypic consequences pharmacological modulation specific target macromolecules. To address this issue, a variety genetic, molecular and chemical tools can be used. All these approaches produce misleading results if specificity not well understood proper controls are performed. In paper we illustrate general themes by providing detailed studies small molecule inhibitors enzymatic activity two members SMYD branch protein...
SETD2, a lysine N-methyltransferase, is histone methyltransferase that plays an important role in various cellular processes and was identified as target of interest multiple myeloma features t(4,14) translocation. We recently reported the discovery novel small-molecule SETD2 inhibitor tool compound suitable for preclinical studies. Herein we describe conformational-design-driven evolution advanced chemistry lead, which resulted compounds appropriate clinical evaluation. Further optimization...
Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and major cause of diarrhea malnutrition. No vaccines or effective drug treatment exist to combat infection. This parasite relies on inosine 5′-monophosphate dehydrogenase (IMPDH) obtain guanine nucleotides, inhibition this enzyme blocks proliferation. Here, we report the first crystal structures CpIMPDH. These reveal structural basis inhibitor selectivity suggest strategy for further optimization. Using...
CARM1 is a type I arginine methyltransferase involved in the regulation of transcription, pre-mRNA splicing, cell cycle progression, and DNA damage response. overexpression has been implicated breast, prostate, liver cancers therefore an attractive target for cancer therapy. To date, little about kinetic properties known. In this study, substrate specificity mechanism human enzyme were determined. Substrate was examined by testing activity with several histone H3-based peptides radiometric...
SET domain-containing protein 2 (SETD2), a histone methyltransferase, has been identified as target of interest in certain hematological malignancies, including multiple myeloma. This account details the discovery EPZ-719, novel and potent SETD2 inhibitor with high selectivity over other methyltransferases. A screening campaign Epizyme proprietary methyltransferase-biased library potential leads based on 2-amidoindole core. Structure-based drug design (SBDD) metabolism/pharmacokinetics...
The protein methyltransferase (PMT) SETDB1 is a strong candidate oncogene in melanoma and lung carcinomas. methylates lysine 9 of histone 3 (H3K9), utilizing S-adenosylmethionine (SAM) as the methyl donor its catalytic activity, has been reported to be regulated by partner ATF7IP. Here, we examine contribution ATF7IP vitro activity substrate specificity SETDB1. were co-expressed 1:1 stoichiometric complexes purified for comparison against enzyme alone. We employed both radiometric...
IMP dehydrogenase (IMPDH) catalyzes two very different chemical transformations, a reaction and hydrolysis reaction. The enzyme toggles between the open conformation required for closed of hydrolase by moving mobile flap into NAD site. Despite these multiple functional constraints, residues site are highly diverged, equilibrium conformations (Kc) varies widely. In order to understand how differences in dynamic properties influence catalytic cycle, we have delineated kinetic mechanism IMPDH...
Allosteric activators are generally believed to shift the equilibrium distribution of enzyme conformations favor a catalytically productive structure; kinetics conformational exchange is seldom addressed. Several observations suggested that usual allosteric mechanism might not apply activation IMP dehydrogenase (IMPDH) by monovalent cations. Therefore, we investigated K(+) in IMPDH delineating kinetic absence Surprisingly, dependence k(cat) derives from rate flap closure, which increases...
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of IMP to XMP via covalent E−XMP* intermediate (E−XMP*), with concomitant reduction NAD+. Hydrolysis is rate-limiting, and catalytic base required for this step has not been identified. An X-ray crystal structure Tritrichomonas foetus IMPDH mizoribine monophosphate (MZP) reveals a novel closed conformation in which mobile flap occupies NAD+/NADH site [Gan, L., Seyedsayamdost, M. R., Shuto, S., Matsuda, A., Petsko, G....
We have identified SRT2104 (4) as the first direct synthetic SIRT1 activator clinical candidate. The compound was derived from optimization of a previously described imidazo[1,2-b]thiazole scaffold. selected development candidate based on combination biochemical activity and pharmacokinetic profile. in vivo characteristics were superior to those analogues with similar activation profiles. overall preclinical profile suggests that has potential provide therapeutic benefit setting.