Research Guides

Department of Chemistry University of Oxford

Professor Angela Russell

Background

The opportunities for chemistry to impact on biology and medicine are essentially limitless. Progress can only occur through collaborations with the life sciences; we have recently instigated a number of collaborations involving more fundamental approaches to the generation of novel drug discovery paradigms, including the study of cellular signalling pathways and their application towards the development of small molecules to manipulate stem cell fate, regenerative medicines and new anti-cancer agents.

Medicinal chemistry for Neuromuscular disease

Collaborative projects include:

Utrophin Modulators for Duchenne Muscular Dystrophywith Professor Dame Kay E. Davies (Department of Physiology, Anatomy and Genetics, University of Oxford) and Summit plc.

It has been shown that utrophin, the autosomal homologue of dystrophin, can compensate for the lack of functional protein in Duchenne Muscular Dystrophy (DMD). The regulation of the transcriptional activity of the utrophin gene has been studied and multiple promoter elements identified that may serve as viable drug targets for pharmacological therapy of DMD, through modulation of utrophin.

Following previous work in the group which led to the development of SMT-C1100, a potential First-in-Class pharmacological therapy for DMD, currently in Phase Ib clinical trials, we have developed a new drug screen using improved in vitro and in vivo screening tools, with the objective being to discover Best-in-Class molecules for the modulation of utrophin. Further screening has identified multiple hit compounds which have both encouraging activity and drug-like properties.

In November 2013 we formed the UtroDMD Alliance, an integrated scientific enterprise involving the University of Oxford, the MDA, the MDC and Summit plc to identify and develop the next generation utrophin modulators. This comprises oral small molecule utrophin modulator SMT C1100 and a pipeline of Next Generation molecules to deliver First-in-Class and Best-in-Class therapies for all DMD Patients. Current efforts within the group are focused on optimising these promising new hits, as well as the use of proteomic technologies to investigate compound mode of action and molecular target.

Stem cell chemistry

The ability to harness the potential of adult stem and precursor cells would be a major advance in the treatment of human disease. Stem cells have been derived from embryo, foetus, umbilical cord, blood, adult tissue, or from the reprogramming of adult somatic cells. They are remarkable cells characterised by their ability to divide and to differentiate via a number of steps to embryonic and adult somatic cell lineages. Such cells thus hold enormous promise both for in vitro screening tools for drug efficacy and toxicity testing, and especially for regenerative therapies treating a wide range of disorders with high unmet medical need such as neurodegenerative diseases, diabetes, heart disease, and vision loss.

The discovery of small molecules to control cell fate has attracted immense interest in recent years. The ability to control each step in proliferation, differentiation and dedifferentiation/ reprogramming processes would allow control of the selective production of different tissue types both in vitro and, importantly in many instances, directly in vivo. The use of chemicals to manipulate cell fate offers many significant advantages over other techniques in terms of speed, cost, reproducibility and the ability to influence cell fate reversibly.

Collaborative projects include:

Pharmacological activation of endogenous stem cell populations for neuroregeneration with Professor Francis Szele (Department of Physiology, Anatomy and Genetics, University of Oxford).

Small molecule activation of the epicardium for cardiac repair with Professor Paul Riley (Department of Physiology, Anatomy and Genetics, University of Oxford).

Small molecule-mediated expansion of human induced pluripotent stem cells with Professor Sally Cowley & Professor William James (Sir William Dunn, University of Oxford).

Cancer medicinal chemistry

Through collaboration with cancer biologists, pharmacologists and structural biologists, the group aims to develop, advance and characterise chemical tools for use as bioprobes and as potential diagnostic agents and therapeutic molecules. We have been focussing on projects that span early stage, though less validated pathways, to projects and targets that are more mature.

 Collaborative projects include:

Chemical Probes for Tumour Biomarker Detection and Inhibition with Professor Edith Sim (Faculty of Science, Engineering and Computing, Kingston University London).

Early detection of breast tumours is known to be critical for improving long-term survival rates. ~70% of breast tumours over-express the estrogen receptor (ER+) and conventional treatments can fail due to intrinsic or acquired resistance. There is a need both for new therapeutic targets and biomarkers to enable rapid, early diagnosis of breast tumours.

Human arylamine N-acetyltransferase 1 (HUMAN(NAT1)) is one of the ten most highly over-expressed genes in ER+ breast tumours, and has been proposed as a candidate diagnostic biomarker and drug target in ER+ breast cancer.

Compound 1, identified by screening as a potent and specific inhibitor of HUMAN(NAT1), was observed to undergo a distinctive colour change (red to blue) upon binding to HUMAN(NAT1) or its murine homologue but not in the presence of any other enzyme tested. A combination of chemical, biochemical and computational studies revealed that this colour change was due to selective binding of the conjugate base species (1-) to HUMAN(NAT1), driven by an ionic interaction with the Arg127 residue.

Further information

For more information about our research, see our group web pages. 

  • Guiraud, S, Squire, SE, Edwards, B, Chen, H, Burns, DT, Shah, N, Babbs, A, Davies, SG, Wynne, GM, Russell, AJ, Elsey, D, Wilson, FX, Tinsley, JM, and Davies, KE. Second-generation compound for the modulation of utrophin in the therapy of DMD.  Hum. Mol. Genet. 2015. doi: 10.1093/hmg/ddv154
  • Taylor, L, Christou, I, Kapellos, TS, Buchan, A, Brodermann, MH, Gianella-Borradori, M, Russell, A, Igbal, AJ, and Greaves, DR.  Primary macrophage chemotaxis induced by cannabinoid receptor 2 agonists occurs independently of the CB2 receptor.Scientific Rep. 2015, doi: 10.1038/srep10682
  • Davies, SG, Kennewell, PD, Russell, AJ, Seden, PT, Westwood, R, and Wynne, GM. Stemistry: the control of stem cells in situ using chemistry.J. Med. Chem. 2015, 58, 2863-2894.
  • Gianella-Borradori, M, Christou, I, Bataille, CJR, Cross, RL, Wynne, GM, Greaves, DR, and Russell, AJ. Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists. Bioorg. Med. Chem. 2015, 23, 241-263.
  • Egleton, JE, Thinnes, CC, Seden, PT, Laurieri, N, Lee, SP, Hadavizadeh, KS, Measures, AR, Jones, AM, Thompson, S, Varney, A, Wynne, GM, Ryan, A, Sim, E, and Russell, AJ.  Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1.  Bioorg. Med. Chem. 2014, 22, 3030–3054
  • Lufino, MMP, Silva, AM, Nemeth, AH, Alegre-Abarrategui, J, Russell, AJ, and Wade-Martins, R.  A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds.  Hum Mol Genet. 2013, 22(25):5173-87.
  • Russell, AJ.  Regenerative medicinal chemistry: the in situ control of stem cells.  ACS Med. Chem. Lett. 2013, 4, 365–368.
  • Laurieri, N, Egleton, JE, Varney, A, Thinnes, CC, Quevedo, CE, Seden, PT, Thompson, S, Rodrigues-Lima, F, Dairou, J, Dupret, J, Russell, AJ, and Sim, E.  A novel color change mechanism for breast cancer biomarker detection: naphthoquinones as specific ligands of human arylamine N-acetyltransferase 1.  PLoS One. 2013 Aug 5;8(8):e70600. doi: 10.1371/journal.pone.0070600
  • Laurieri, N, Crawford, MHJ, Kawamura, A, Westwood, IM, Robinson, J, Fletcher, AM, Davies, SG, Sim, E, and Russell, AJ.  Small molecule colorimetric probes for specific detection of human arylamine N-acetyltransferase 1, a potential breast cancer biomarker.J Am Chem Soc.  2010, 132(10):3238-9.
  • Soncin, F, Mohamet, L, Eckardt, D, Ritson, S, Eastham, AM, Bobola, N, Russell, A, Davies, S, Kemler, R, Merry, CLR, and Ward, CM.  Abrogation of E-cadherin-mediated cell-cell contact in mouse embryonic stem cells results in reversible LIF-independent self-renewal.Stem Cells. 2009, 27(9):2069-80.
  • Wilkinson, RN, Pouget, C, Gering, M, Russell, AJ, Davies, SG, Kimelman, D, and Patient, R.  Hedgehog and Bmp polarize hematopoietic stem cell emergence in the zebrafish dorsal aorta. Dev Cell. 2009, 16(6):909-16