|Figure 1. Target discovery is the first step in drug discovery A. Comparison of the genes of diseased versus healthy cells can uncover new drug targets. B. RNA interference (RNAi) can show that a potential drug target (red) is responsible for the disease. C. A chemical probe can show that a single region of the drug target (red crescent) is the culprit and the probe can be optimised to give a new medicine.|
|Figure 2. Epigenetic marks on histones A lysine demethylases (KDM, red hexagon) removes an epigenetic mark (red) from histone (green). A plant-homeodomain (PHD, red crescent) reads the epigenetic mark. A bromodomain (BRD, purple crescent) reads another epigenetic mark (purple). The epigenetic marks regulate the gene encoded in the DNA (blue).|
Professor of Medicinal Chemistry
We are a research group working at the interface of chemistry and biology to design probes and inhibitors to investigate the intricate workings of human proteins and cells, with particular interest in epigenetics and dementia. We form part of the Alzheimer's Research UK Oxford Drug Discovery Institute (ODDI) at the University of Oxford.
Epigenetic Chemical Probes in Drug Discovery
The major cause of failure in discovery of new medicines is due to a fundamental lack of understanding of the biology of disease. The likelihood of a new medicine having a positive effect when tested in patients for the first time is less than 30%. In order to find new medicines for diseases, like Alzheimer’s disease, cancer and chronic inflammation, we first need to discover a new novel disease-associated protein target. Following on from the discovery of a target, drug discovery is aimed at finding safe, effective means of modifying the target’s detrimental effects in disease.
Target Discovery currently uses a number of tools to associate a protein target with a disease: genetic comparisons of diseased versus healthy individuals (figure 1A); inhibition of every possible expressed gene in a cellular model of a disease (a process known as RNA interference - RNAi, figure 1B); or the use of chemical probes in cellular or animal disease models (figure 1C). None of these approaches is perfect. Genetic comparisons are confounded by functional redundancy of genes, multiplicity of genetic effects and environmental factors. RNA interference removes an entire protein target when only a small piece of it may be important in the disease and the rest is necessary for normal, healthy functions.
Chemical probes are available for only a small fraction of potential disease targets and are usually less specific than RNAi. The scarcity of chemical probes is disappointing as they are especially useful; a probe that shows a positive effect can also serve as a chemical starting point for drug discovery. If genetic or RNA interference methods identify an exciting disease target, it may still take many years to find a chemical starting point to move from target discovery to drug discovery, whereas using a chemical probe in target discovery jump-starts the process.
Epigenetics is an exciting new arena for target discovery. Classically epigenetics is defined as the transfer of heritable traits from parent to off-spring other than by genetic means. Understanding of the molecular processes of the epigenetic phenomena has led to an expanded definition. Epigenetics can now be thought of as the control of gene expression via chemical marks which are written, read and erased by regulating proteins. The largest variety of epigenetic marks is written on histones (figure 2). Histones are proteins necessary to accomplish one of nature’s greatest feats: packaging two metres of DNA into a single cell which is 0.00001% as long. Like a spool, the long threads of DNA (blue in figure 2) are wrapped around a histone core (green in figure 2). Histones not only package the DNA, but they also control it. In our thread and spool analogy, the spool can be programmed with epigenetic enzymes to decide when the thread should be unwound and used in gene transcription.
Epigenetic control of genes is a complex system of regulation by hundreds of enzymes that have multiple functions. There are multiple epigenetic chemical marks and the combination of marks creates an epigenetic code, similar in concept but even more complex than the genetic code of DNA. Since problems with control of gene expression are fundamental to many diseases, for example cancer, inflammation and neurological conditions, and enzymes control is the most common action of medicines, epigenetics offers a fortuitous meeting of disease biology with drug discovery capabilities and is generating unprecedented excitement in the global medical research community. But target discovery in epigenetics is more difficult than other areas. There is limited evidence from genetic comparisons of important epigenetic targets. It is hard to interpret the results of RNAi experiments as the entire enzyme is removed and epigenetic enzymes have multiple regions with multiple purposes. The few successful epigenetic drugs which are known affect only a single enzyme region. What the field of epigenetic drug discovery desperately needs is the chemical probes to use in target discovery.
Research in our group is focussed on discovery of chemical probes for three classes of epigenetic enzymes, lysine demethylases (KDM, red hexagon in figure 2), plant-homeodomains (PHD, red crescent in figure 2) and bromodomains (BRD, purple crescent in figure 2). There are over twenty KDMs and they collectively erase chemical marks important in gene regulation. One of the KDMs, KDM4B is potentially import in breast cancer and the chemical probe my research group is developing will provide a chemical starting point for drug discovery if it proves the link between KDM4B and breast cancer. PHDs read the same chemical mark that is erased by KDMs. Reading of the epigenetic mark by PHDs is involved in gene transcription but there are hundreds of PHDs and the biology of most is a mystery. There are more than sixty BRDs and they recognize a different epigenetic mark to the KDM/PHD system. At least some of the BRDs are involved in many cancers.
Our Medicinal Chemistry group utilises high-throughput and fragment-basedscreening to discover chemical leads. The leads are optimised for potency, selectivity and cellular activity via iterative cycles of structure based drug design, parallel organic synthesis, biophysical testing and compound structure-activity relationship (SAR) analysis.
The chemical probes developed in the group will decipher the function of epigenetic proteins in disease and provide starting points for drug discovery. By using epigenetic chemical probes in target discovery, we will dramatically accelerate drug discovery in one of the most promising new areas of biomedical research.
A phenotypic high-content, high-throughput screen identifies inhibitors of NLRP3 inflammasome activation
Nizami S. et al, (2021), Scientific Reports, 11
The structural basis of fatty acid elongation by the ELOVL elongases
Nie L. et al, (2021), Nature Structural & Molecular Biology, 28, 512 - 520
Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia
Mackinnon SR. et al, (2021), ACS Chemical Biology
RHO to the DOCK for GDP disembarking: structural insights into the DOCK GTPase nucleotide exchange factors.
Thompson AP. et al, (2021), The Journal of biological chemistry
Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity.
Doss PMIA. et al, (2021), Cell reports, 34