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Fuchter group. Chemical Synthesis
Department of Chemistry, Imperial College London, South Kensington Campus. London SW7 2AZ, UK
United Kingdom

Acetylation, methylation, inhibitor, probe, histone




Synthetic medicinal chemistry, computer assisted drug design, biochemistry

Collaborations outside COST

We have a wide range of on-going collaborations; some detailed below.

Short description of ongoing research projects

The Fuchter group have a wide-ranging track record in the design, synthesis and application of small molecule probes to biological systems, especially against epigenetic targets. Current activities include: 1. Epigenetic inhibitor development. Through hypothesis driven medicinal chemistry we have made significant progress in the discovery of unique and unprecedented small molecule inhibitors of epigenetic enzymes. Published outputs include highly ligand efficient HDAC inhibitors (ChemMedChem 2013), highly isoform selective SIRT inhibitors (MedChemComm, 2012 and ChemMedChem, 2014), quinazoline dual EZH2/EHMT2 HKMT inhibitors (Clin. Epigenetics, in press) and quinoline EHMT1/2 inhibitors (MedChemComm 2014). Working closely with a range of collaborators, we have used these molecules to provide novel opportunities in therapy. Current efforts include the application of our probes in cancer (with Prof. Bob Brown, Imperial), Parkinson's disease (with Prof. David Dexter, Imperial College), and chronic pain (with Dr Pete DiMaggio and Neusentis Ltd). Our studies are not limited to human enzymes however, and we are also actively targeting homologous proteins/pathways in parasites which cause human disease: for example T. brucei (which causes African sleeping sickness) and Plasmodium (which causes malaria). For example, we were the first to discover Plasmodium histone methyltransferase (PfHKMT) inhibitors that result in blood stage independent parasite killing (PNAS 2012 and ChemMedChem 2014) and have an unprecedented ability “reawaken” dormant liver stage parasites (Nature Med. 2014). 2. Epigenetic probe mechanism of action. Using enabling synthetic medicinal chemistry and biochemistry, we continue to unambiguously determine the mechanism of action of several epigenetically active small molecules, including naturally isolated products. Examples include the fungal metabolite chaeotcin (Nature Chem. Biol. 2013, J. Med. Chem 2013) and the marine natural product psammaplin A (J. Med. Chem. 2012). 3. Novel chemical biological approaches in epigenetics. In mostly unpublished work, we have a number of on-going projects, particularly funded by the Institute of Chemical Biology, surrounding the development of chemical biological tools that would enable better biological understanding of epigenetic events. These include a novel technology to map the “methylome” maintained by specific HKMTs (with Dr Pete DiMaggio) and a unique chemical means to map histone trimethylation (with Dr Pete DiMaggio and Dr Till Bartke). We are also developing novel epigenetic imaging agents to facilitate our studies aimed at validating these important targets in disease.

  1. "The Discovery of a Highly Selective 5,6,7,8- Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model" Di Fruscia, P.; Zacharioudakis, E.; Liu, C.; Moniot, S.; Laohasinnarong, S.; Khongkow, M.; Harrison, I. F.; Koltsida, K.; Reynolds, C. R.; Schmidtkunz, K.; Jung, M.; Chapman, K. L.; Steegborn, C.; Dexter, D. T.; Sternberg, M. J. E.; Lam, E. W.-F.; Fuchter, M. J.* ChemMedChem 2015, 10, 69
  2. "Identification of 2,4-Diamino-6,7-dimethoxyquinoline derivatives as G9a Inhibitors" Srimongkolpithak, N.; Sundriyal, S.; Lu, F.; Vedadi, M.; Fuchter, M. J.* Med. Chem. Commun. 2014, 5, 1821
  3. "Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases" Cherblanc, F.; Chapman, K. L.; Brown, R,; Fuchter, M. J.* Nature Chem. Biol. 2013, 9, 136
  4. "Highly Ligand Efficient and Selective N-2-(Thioethyl)picolinamide Histone Deacetylase Inhibitors Inspired by the Natural Product Psammaplin A" Baud, M. G. J.; Haus, P.; Leiser, T.; Meyer-Almes, F. -J.; Fuchter, M. J.* ChemMedChem, 2013, 8, 149
  5. "Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum" Malmquist, N. A.; Moss, T. A.; Mecheri, S.; Scherf, A.*; Fuchter, M. J.* P. Natl. Acad. Sci. USA 2012, 109, 16708
Other activities of potential interest to others

We also work in other areas of medicinal chemistry, drug discovery, chemical biology and imaging. Furthermore, we have active efforts in the area of chiral organic materials (which could lead to sensor technologies, etc).

Cost UE