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High Throughput Chemistry (HTC) - Articles and news items
The last 10 years in biomedical research marks the period of deepening our understanding of the human genome. In the context of cancer research, The Cancer Genome Atlas (TCGA) and related international genomics efforts have now revealed the full complexity of genomic aberrations in human cancers that are postulated to contribute to the aspects of cancer pathophysiology. It is plausible that an ensemble of the numerous aberrations in each individual tumour collaborate at various strengths to deregulate master signalling pathways of cells, thereby enabling the established cancer ‘hallmarks’.
The histone deacetylase (HDAC) class of enzyme are a group of conserved enzymes known for their ability to remove acetyl groups from lysine residues on histone tails. Since aberrant HDAC enzyme expression is observed in various diseases, there is increasing interest in finding small molecules which function as HDAC enzyme inhibitors. This article reviews the various biochemical assays available for monitoring HDAC enzyme activity that have been validated for use in High Throughput Screening. The assays referred to are compatible with standard microtitre plates (96 and 384 well format) and make use of absorbance, luminescence and fluorescence detection methods.
The histone deacetylase class of enzymes: The histone deacetylase (HDAC) class of enzymes are involved in many biological pathways and one of their best known properties is their ability to remove acetyl groups from lysine residues on amino-terminal histone tails. Thus far, 18 HDAC enzymes have been identified which are divided into zinc dependent and NAD dependent enzymes. The Class I HDAC enzymes include the zinc dependent HDACs 1, 2, 3, and 8 and consist of 350-500 amino acid residues. The Class II HDAC enzymes are also zinc dependent but are larger, consist of about 1,000 amino acid residues and are subdivided into Class IIa (HDAC4, 5, 7, and 9) and Class IIb (HDAC6 and HDAC10) enzymes. The Class I and Class II HDAC enzymes can be inhibited by trichostatin A (TSA) and this inhibitor is often used as a reference to bench-mark their assays. The Class III HDAC enzymes are the sirtuin enzymes (SIRT1-7) and are NAD-dependent. This class of enzymes is not sensitive to TSA but can be inhibited for example by nicotinamide.
This article describes the evolution of outsourcing within early drug discovery at GlaxoSmithKline (GSK), specifically for chemistry services applied to developing a compound from the screening hit through lead optimisation. It will touch on different business models, factors to consider when selecting potential CROs, the benefits of outsourcing and CRO management…
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