People

Dr Richard Doveston

Lecturer in Chemical Biology and Chemistry MSc Coordinator

School/Department: Chemistry, School of

Telephone: +44 (0)116 229 7116

Email: rd306@leicester.ac.uk

Profile

I obtained a MChem degree in Pharmaceutical Chemistry here at University of Leicester in 2008 before going on to complete a PhD in the group of Prof. Richard Taylor at the University of York. My PhD involved developing a synthetic route to the natural product janoxepin. Following this I took up a post-doctoral position with Prof. Adam Nelson and Prof. Steve Marsden at the University of Leeds to work in the area of ‘lead-oriented synthesis’. I then joined the Chemical Biology Group at the Technical University of Eindhoven (NL) and was there awarded a Marie Curie Fellowship in 2016. My research carried out under Prof. Luc Brunsveld and Dr. Christian Ottmann was focused on the discovery and evaluation of novel bioactive small molecules with a particular interest in using molecular glues to stabilise protein-protein interactions. I established my research group in the School of Chemistry and Leicester Institute of Structural and Chemical Biology in 2018. We are interested in continuing to understand and exploit the chemistry behind molecular glues in a pharmaceutical context. We take an interdisciplinary approach working closely with structural biologists and cell biologists.

Research

My group has three broad research themes all focused on accelerating the development of molecular glues as novel drug molecules. Most of our work uses a family of important 'hub' proteins called 14-3-3. These proteins interact with many other proteins and a number of these interactions can be stabilised by small molecules. The themes are:

1. Discovering molecular glues: currently it is hard to discover new molecular glues. We are developing new screening technologies (e.g. native mass spectrometry fluorescence-based methods) to overcome this problem.

2. Targeting 14-3-3 proteins in cancer: 14-3-3 protein interactions are great drug targets in particular for cancer. We work with collaborators to find new and more selective ways to target 14-3-3.

3. Novel bifunctional molecules: we are interested in developing bifunctional molecules that bring two protein targets together to elicit novel biological responses. We have received funding from the Royal Society the Royal Society of Chemistry and the University of Leicester Institute of Advanced Studies (10x10 Fund) to establish this exciting research programme. Our laboratories are housed in the Henry Wellcome Building.

Publications

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Discovering Protein-Protein Interaction Stabilisers by Native Mass Spectrometry J. Bellamy-Carter M. Mohata M. Falcicchio J. Basran Y. Higuchi R.G. Doveston* A. C. Leney* Chem. Sci. 2021 12 10724-20731.

Regulation of p53 by the 14-3-3 Protein Interaction Network: New Opportunities for Drug Discovery in Cancer M. Falcicchio J. A. Ward S. Macip R. G. Doveston* - Cell Death Discovery 2020 6 126.

Adoption of a Turn Conformation Drives the Binding Affinity of p53 C-Terminal Domain Peptides to 14-3-3σ A. Kuusk J. F. Neves K. B. Rodriguez A. Gunnarsson. Y. B. Ruiz-Blanco M. Ehrmann H. Chen* I. Landrieu* E.Sanchez-Garcia* H. Boyd* C. Ottmann* R. G. Doveston* - ACS Chem. Bio. 2020 262-271.

Cooperativity in Ligand Binding between the Orthosteric and Allosteric Binding Sites of RORγt R. M. J. M. de Vries F. A. Meijer R. G. Doveston I. A. Leijten-van de Gevel L. Brunsveld Proc. Nat. Acad. Sci. 2021 118 e2021287118.

Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site F. A. Meijer M. C. M. van den Oetelaar R. G. Doveston E. N. R. Sampers L. Brunsveld ACS Med. Chem. Lett. 2021 12 631-639.

Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt F. A. Meijer A. O. W. M. Saris R. G. Doveston G. J. M. Oerlemans R. J. M. de Vries B. A. Somsen A. Unger B. Klebl C. Ottmann P. J. Cossar L. Brunsveld J. Med. Chem. 2021 64 9238-9258.

Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site F. A. Meijer M. C. M. van den Oetelaar R. G. Doveston E. N. R. Sampers L. Brunsveld ACS Med. Chem. Lett. 2021 12 631-639.

Ligand-based Design of Allosteric RORγt Inverse Agonists R.G. Doveston F. A. Meijer R. M. J. M. de Vries G. Vos A. Vos M. Scheepstra S. Leysen C. Ottmann L.-G. Milroy and L. Brunsveld - J. Med. Chem. 2020 241-259.

Elucidation of an Allosteric Mode-of-Action for a Thienopyrazole RORgt Inverse Agonist R. M. J. M. de Vries R. G. Doveston F. A. Meijer L. Brunsveld - ChemMedChem 2020 561-565.

Small Molecule Modulators of 14-3-3 Protein-Protein Interactions L. M. Stevers E. Sijbesma M. Botta C. MacKintosh T. Obsil I. Landrieu A. J. Wilson A.Karawajczyk J. Eickhoff J. Davis M. Hann G. O’Mahony M. Perry R. G. Doveston L. Brunsveld C. Ottmann - J. Med. Chem. 2018 3755-3778.

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Supervision

I am very happy to supervise PhD students who would like to work in the field of chemical biology or medicinal chemistry. Please get in touch to discuss what projects are currently available in the group.

Teaching

I am the Chemistry MSc programme coordinator and convene the following MSc modules:

  • CH7360 Advanced Research Communication and Skills 
  • CH7361 Advanced Practical Skills
  • CH7361 MSc Research Project

Undergraduate modules:

  • CH3211 Pharmaceutical Chemistry - module convenor
  • CH3271 Advanced Synthetic Techniques Practical Course - module convenor
  • CH4202 Advanced Synthetic Methods - lecturer
  • CH3205 Metals in Synthesis (DLI ) - lecturer

I also help to deliver organic chemistry tutorials and workshops for first and second year undergraduate courses.

Press and media

Emerging concepts in drug discovery/development 14-3-3 proteins molecular glues

Media coverage

https://themedicinemaker.com/discovery-development/marrying-up-proteins-using-molecular-glues https://www.youtube.com/watch?v=5nK7hWesUf8 

Qualifications

Fellow of the Higher Education Academy (FHEA)
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