Research in the group is divided between two interlinked areas: pioneering new reactions and the development of new medicinal drug molecules.
1. Organic Synthetic Methodology
This area of our research focuses on the development of novel organic synthetic methodology for assembling structural motifs common in drug-like molecules. With the development of new reactions, pharmaceutical chemists are able to pursue faster, cheaper and more efficient syntheses of existing drugs. Our new reactions revolve around utilizing directed metalation to install new substituents onto a molecule: thus, using a group 1 or 2
organometallic reagent, a Lewis-basic directing group directs metalation onto an adjacent position, and the new substituent (R) is then installed either by electrophilic trapping or via transition metal catalysed cross coupling. Our investigations in this field utilize novel directing groups which are typically installed at a late stage during synthesis. Thus, the new reactions we develop are amenable for use in late-stage modifications of drug-like molecules, and enable medicinal chemists to rapidly build libraries of lead-compound analogues, a vital process during drug development.
2. Medicinal and Bioorganic Chemistry
We are involved in a number of collaborative projects focused on developing new small molecule ligands for key cellular signalling process enzymes.
2.1 Non-Cyclic Nucleotide Ligands for EPAC1
EPAC1 is a cellular signalling enzyme which mediates downstream biological responses through interaction with the Ras-like GTPases Rap1 and Rap2 in response to the presence of cyclic AMP (cAMP). Under normal conditions, binding of cAMP induces a conformational change in EPAC1, allowing docking of a Rap protein. While EPAC1 is known to play a role in such conditions as atherosclerosis, insulin resistance, and tumour metastasis, drugs based on cAMP suffer from ready metabolism and off target side effects from interaction with EPAC2 and PKA. In collaboration with Dr. Stephen Yarwood and Prof. David Adams, we are developing novel non-cyclic nucleotide small molecule ligands for EPAC1 with both agonist and antagonist properties.
2.2 PTEN Antagonists
PTEN is a tumour-suppresant enzyme which acts by hydrolysing the cellular signalling phospholipid PIP3. While around 70% of prostate cancer patients have lost a copy of the gene encoding PTEN, it has been shown that deliberate PTEN suppression can aid axon regrowth following nerve damage. In collaboration with Dr. Nick Leslie and Prof. David Adams, we are investigating new PTEN inhibitors with the aim of developing new therapies for spinal chord damage.