Medicinal Chemistry

There is huge potential for chemistry to have an enormous impact on the biological and medicinal world. We have several highly successful multidisciplinary research collaborations including the development of small molecules to determine stem cell fate, novel protein tyrosine phosphatase inhibitors for treatment of cancer and transcriptional upregulation of utrophin in the treatment of Duchenne Muscular Dystrophy (DMD).
 

Medicinal Chemistry
 

Stem Cells (Stemistry)

Harnessing the potential of stem cells is one of the next major challenges in medicine and healthcare. The control of a stem cells fate with the use of small molecules to control the destiny of stem cells is an emerging discipline which offers unprecedented advantages over other techniques in terms of speed, cost, reproducibility and the ability to influence stem cell fate reversibly. We have recently developed a set of small molecules capable of embryonic stem cell proliferation in the absence of protein-based growth factors.
 

 Stemistry
 

Current work within the group is investigating the use of small molecules on the directed differentiation pathways of pluripotent eSCs down specific lineages towards specialised tissue types such as neurons and cardiomyocytes. We have strong collaborations with the Oxford Stem Cell Institute and the British Heart Foundation Centre of Research Excellence, working with Angela Russell (Departments of Chemistry and Pharmacology), Paul Riley (Department of Physiology, Anatomy and Genetics), Robert MacLaren (Nuffield Laboratory of Ophthalmology), William James (Sir William Dunn School of Pathology), Roger Patient (Weatherall Institute of Molecular Medicine), Mathew Wood (Department of Physiology, Anatomy and Genetics), Suzanne Watt (Nuffield Department of Clinical Laboratory Sciences), and Francis Szele (Department of Physiology, Anatomy and Genetics). We are also currently collaborating on a recently awarded €55.6m EU FP7 Innovative Medicines Initiative Grant: StemBANCC, Stem Cells for Drug Discovery, led by Zameel Cader (Department of Clinical Neurology, Oxford).

This work has been funded by the BBSRC, EPSRC and the British Heart Foundation.

Key Publications:

  1. Stemistry: the control of stem cells in situ using chemistry
    Davies, S. G.; Kennewell, P. D.; Russell, A. J.; Seden, P. T.; Westwood, R.; Wynne, G. M. J. Med. Chem. 201558, 2863 [View Journal Page]
  2. Hedgehog and Bmp Polarize Haematopoietic Stem Cell Emergence in the Zebrafish Dorsal Aorta Wilkinson R. N.; Pouget C.; Gering M.; Russell A. J.; Davies S. G.; Kimelman D.; Patient R. Developmental Cell, 2009, 16, 909 [View Jounal Page]
  3. Abrogation of E-cadherin Mediated Cell-cell Contact in Mouse Embryonic Stem Cells Results in Reversible LIF-independent Self Renewal Soncin F.; Mohamet L.; Eckardt D.; Ritson S.; Eastham A. M.; Bobola N.; Russell A. J. Davies S. G.; Kelmer R.; Marry C. L.; Ward C. M. Stem Cells, 2009, 27, 2069
    [View Journal Page]

Duchenne Muscular Dystrophy

It has been shown that utrophin, the autosomal homologue of dystrophin can compensate for the aberrantly regulated protein in Duchenne Muscular Dystrophy (DMD). In collaboration with Professor Kay Davies (Department of Physiology, Anatomy and Genetics) we have identified several classes of small molecules which up-regulate utrophin expression in a dose-dependent fashion.
 

DMD
 

This work has led to the development of SMT C1100 by Summit plc, currently undergoing a Phase 1b clinical trial in DMD patients as a First-in-Class pharmacological therapy. We have been working towards follow-on compounds and in November 2013 we entered a strategic alliance with Summit plc. As part of the collaboration, Summit will sponsor a drug discovery programme in our laboratories to identify and develop additional utrophin modulator drugs to deliver a Best-in-Class therapy for DMD.

 

 

 

 

 

 


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