A life in Fragments: from Chemical Biology to Drug Discovery

Fragment-based lead discovery (FBLD) is now firmly established as a mature collection of methods and approaches for the discovery of small molecules that bind to protein or nucleic acid targets.  The approach is being successfully applied in the search for new drugs, with many compounds now in clinical trials (see summary in1) and with the first fragment-derived compounds now treating patients2,3.  The approach has also had a number of other impacts such as providing starting points for lead discovery for challenging, unconventional targets such as protein-protein interactions3-5 and providing small groups, particularly in academia, with access to the tools to identify chemical probes of biological systems6,7.
The central feature of FBLD is that the drug discovery process begins with identification (usually by biophysical methods) of small (<250 MW), weakly binding (affinity of 100s of µM) compounds which are then optimised to drug candidates by structure-guided design8-10.  The advantages are that a small library can sample a potentially large chemical diversity to generate multiple novel lead series of compounds and that hits can be identified for new classes of target for which existing compound collections cannot provide a hit. 
In this talk, I will start with a brief summary of the current methods and practises in FBLD.  I will then spend most of the time discussing how the ideas and methods have impacted chemical biology and lead discovery.  This will draw on experiences from research at York and from projects at Vernalis.  The examples will include work on conventional targets such as kinases and how the methods have evolved to tackle nonconventional targets such as new classes of enzyme and disruption of protein-protein interactions.

Rod Hubbard has been working with methods for analysis and exploitation of protein structure for nearly 35 years.  In the 1980s, he developed molecular graphics and modelling methods.  In the 1990s he helped build the Structural Biology Lab at the University of York and determined the structure of many proteins of therapeutic importance; this was combined with studies of protein-ligand interactions and some of the first work in finding small fragments that bind to protein targets.  In 1997, he was a founding SAB member of the structure-based pharmaceutical company that became Vernalis.  Since 2001, he has spent varying amounts of his time at Vernalis, establishing and applying structure and fragment-based methods for drug discovery.  He currently splits his time between York and Vernalis; in addition, he is a member of various boards and panels for the UK Research Councils and consults with pharmaceutical and technology companies around the world.

1.             Erlanson, D. A.; Zartler, E. Practical Fragments Blog. http://practicalfragments.blogspot.com/ 2013.
2.             Bollag, G. et al.  Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov 2012, 11, 873-86.
3.             Souers, A.J., et al., ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nature medicine, 2013. 19, 202-208.
4.             Sun, Q.; Burke, J. P.; Phan, J.; Burns, M. C.; Olejniczak, E. T.; Waterson, A. G.; Lee, T.; Rossanese, O. W.; Fesik, S. W. Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation. Angewandte Chemie-International Edition 2012, 51, 6140-6143.
5.             Ostrem, J. M.; Peters, U.; Sos, M. L.; Wells, J. A.; Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013, 503, 548-51.
6.             Yin, Z.; Whittell, L. R.; Wang, Y.; Jergic, S.; Liu, M.; Harry, E. J.; Dixon, N. E.; Beck, J. L.; Kelso, M. J.; Oakley, A. J. Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach. Journal of Medicinal Chemistry 2014, 57, 2799-806.
7.             Darby, J. F.; Landstrom, J.; Roth, C.; He, Y.; Davies, G. J.; Hubbard, R. E. Discovery of selective small-molecule activators of a bacterial glycoside hydrolase. Angewandte Chemie 2014, 53, 13419-23.
8.             Schulz, M.N., Hubbard, R.E., Recent progress in fragment-based lead discovery Curr Opin Pharmacol 2009, 9, 615-21
9.             Hubbard, R.E., Murray, J.B. Experiences in fragment-based lead discovery Methods Enzymol 2011, 493, 509-31
10.           Erlanson,D., Fesik, S., Hubbard, R.E., Jahnke, W., Johti, H., Twenty years on: the impact of fragments on drug discovery 2016, Nature Rev Drug Discovery, in press

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Dr Simon Cook
The Brian Heap Seminar Room