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Epigenetics


histone demethylase (HDM) activity. The kits focus on several key epigenetic targets and include four different DNMT kits, 16 HMT kits, six HDM kits, three HDAC kits, six poly [ADP Ribose] poly- merase (PARP) kits (including Tankyrase 1 and 2), as well as a HAT (histone acetyltransferase) assay. PARP is involved in chromatin remodelling and control of DNA methylation, and PARP and its isozymes are products unique to BPS. In addition to providing assay kits and enzymes, BPS also offers screening and profiling services to determine the IC50 of test compounds or to screen an inhibitor against a panel of active enzymes. BPS’s enzyme profiling panel currently includes all 11 HDACs, four SIRTs, six PARPs, 15 HMTs, three DNMTs and four HDMs (Figure 14).


Figure 14: IC50 assay of PARP5A (TNKS1) enzyme activity, using PARP inhibitor AZD2281, measured using BPS Bioscience’s Tankyrase-1 Chemiluminescent Assay Kit, #80565. Luminescence was detected using a Bio-Tek fluorescent microplate reader. IC50 = 1.93µM


co-expressed as a complex of five different proteins (EZH2, EED, SUZ12, RbAp48 and AEBP2) to maximise activity. Similarly, its DNA methyltrans- ferase (DNMT) 3A and 3B enzymes are co- expressed with the regulatory factor DNMT3L, resulting in a functional complex similar to the native conformation of these proteins. These and other enzymes are the basis of a sequential panel of unique assays that allow researchers to assess the total epigenomic state of a cell, as well as study individual pathways. These kits estimate levels of cellular DNA methylation and histone methyla- tion/demethylation by measuring DNA methyl- transferase, histone methyltransferase (HMT) and


Cayman Chemical (www.caymanchem.com) now offers an Epigenetics Lead Discovery Service, a col- laborative programme for identifying novel epige- netic therapeutics by screening against a panel of targets. This Service places three Cayman strengths to your advantage. First, a Protein Core Team pro- duces pure and functional recombinant proteins. Over 25 different proteins, including human HDACs, SIRTs, KMTs, KDMs and histones, are currently available. Second, an Assay Development Group creates versatile, dependable and affordable assay kits for each enzyme. To date, they have developed assay kits containing SIRT1, SIRT2, SIRT3, SIRT6, HDAC8, LSD1, SET7/9, SET8, JMJD2A and JMJD2D; these are designed to screen compounds that might alter activity. Other available assays measure overall DNA methyla- tion, SAM-dependent methyltransferase activity, and JmjC- or LSD-type KDM activity. Finally, Cayman’s outstanding chemists synthesise the lat- est inhibitors and modulators for epigenetics research. These products can be found on Cayman’s website and purchased individually. However, independent researchers and companies alike have successfully worked with Cayman chemists for assistance in route design, hit-to-lead chemistry and scale-up synthesis for preclinical studies. Now, Cayman has established a dedicated screening lab to help meet epigenetics research and development needs (Figure 15).


Figure 15: Cayman Epigenetics Lead Discovery (CELD) services will continually expand capabilities to other core areas of Cayman expertise


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Chromatin modulations play a central role in shap- ing the epigenome and many of the enzymes that mediate the covalent modification of the DNA and the protein components of the chromatin are deregulated in human diseases. Antibody or small molecule-based interventions modulating the activ- ity of the DNA/chromatin-modifying enzymes


Drug Discovery World Spring 2011


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