Abstract

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Although investment in pharma for the discovery of new medicines has increased exponentially over the past three decades, this is not reflected in the rate of new drug approvals. Much of the research activity has been focused on superfamilies of protein targets, including protein kinases, proteases and ATPases. This lecture will explore the idea that we should instead target the multiprotein assemblies that regulate cell activity. These vary widely within superfamilies and inhibitors have the potential to be more selective and therefore less likely to lead to off-target effects that contribute to drug failure in development.

I will focus on the use of fragment-based approaches to making chemical tools and candidate therapeutic molecules – an approach pioneered by the company I cofounded with Chris Abell and Harren Jhoti, Astex http://www.cam.ac.uk/research/news/astex-pharmaceuticals-acquired-by-otsuka.

I will describe work in our academic labs on classical allosteric inhibitors – the modulation by recognition of a site distant from the active site of conformation in a molecule or assembly – and those that disturb co-location by disrupting multi protein assemblies. The targets, which have been defined by basic research funded by the Wellcome Trust and MRC , will include cell surface receptors such as FGFR , a target in cancer, and Met, of particular interest in controlling metastasis of tumours. I will also discuss targeting human recombinase, Rad51, through interactions with BRCA2 , inhibitors of which would be helpful in modulating DNA repair during chemo- or radiotherapy.

Collaborations have included labs of C Abell and J Skidmore in Chemistry, A Venkitaraman and G McKenzie in Oncology, E Gherardi in MRC centre and Pavia and Hyvonen in Biochemistry, Cambridge.