Structure Based Drug Discovery

Hsp90 ATPase Inhibitors

We use our understanding of the structural biology and biochemistry of the Hsp90 molecular chaperone system to facilitate discovery and development of competitive inhibitors of its ATP utilisation. These compounds block maturation of many oncogenic protein kinases that depend on Hsp90 for the function, and are showing promise as drugs in a range of cancer types.

Our seminal work opening up Hsp90 as a target for therapy in cancer was recognised by the award of the 2013 Cancer Research UK Translational Cancer Research Prize

Projects include :

• Diarylpyrazole and diarylisoxazole inhibitors - NVP-AUY922 now in Phase II Clinical Trial by Novartis
• Biosynthetically engineered ansamycin inhibitors, in collaboration with Biotica Technology Ltd
• Synthetic resorcylic macrolactone inhibitors, in collaboration with Chris Moody, U. of Nottingham
• Structural basis of resistance in fungi and streptomycetes that synthesise Hsp90-inhibitors

DNA Repair and Damage Signalling Inhibitors

Many cancers have defects in DNA repair pathways that underlie their disregulated phenotype, but make them susceptible to further DNA damage and inhibition of parallel pathways. We are involved in development of new inhibitors of DNA repair enzymes for treatment of cancer.

Projects include :

• Inhibitors of the DNA damage signalling protein kinase CHK2, in collaboration with CR-UK Cancer Therapeutics, ICR 
• Inhibitors of the poly(ADP-ribose) polymerase enzyme Tankyrase, in collaboration with Breakthrough Breast Cancer
• Inhibitors of the DNA end-processing enzyme polynucleotide kinase 3'-phosphatase (PNK)
• Inhibitors of the DNA end-processing enzymes Tdp1 and Tdp2
• Inhibitors of Greatwall mitotic entry kinase (GWL/MASTL3)

GSK3β Inhibitors

In collaboration with Laurent Meijer we have characterised the structural basis for the action of a number of ATP-competitive inhibitors of GSK3β derived from marine organisms and high-throughput screens :

• Indorubins
  
• Leucettines
  
• 3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles - specific for Plasmodium GSK3β