RSB Directors Seminar: Structure-guided Fragment-based Drug Discovery for Cancer and Tuberculosis: Fighting the Emergence of Resistance

Presented by ANU College of Science

Knowledge derived from genome sequences of humans and pathogens has the potential to accelerate diagnosis, prognosis and cure of disease. We are moving quickly into an era of precision medicine, not only in familial diseases where a mutation in a human gene is important, but also for understanding somatic mutations in cancer.  Equally important, the genome sequences of pathogens, for example in tuberculosis or leprosy, can give clues about the choice of existing drugs, repurposing of others, and the design of new ones to combat the increasing occurrence of drug resistance. 

One approach is to exploit state-of-the-art methods to bring new drugs for different targets to the market, but this will be difficult to finance if patient populations are small. Structure-guided fragment-based screening techniques have proved effective in lead discovery not only for classical enzyme targets but also for less "druggable" targets such as protein-protein interfaces. Initial screening involves small fragments with very low, often millimolar affinities, and biophysical methods including X-ray crystallography are used to explore chemical space of potential ligands. The approach involves a fast initial screening of a library of around 1000 compounds, followed by a validation step involving more rigorous use of related methods to define three-dimensional structure, kinetics and thermodynamics of fragment binding.

The use of high throughput approaches, with X-ray synchrotron sources playing a major role, does not end there, as it becomes a rapid technique to guide the elaboration of the fragments into larger molecular weight lead compounds. I will discuss progress in using these approaches for targets  in cancer and in mycobacteria tuberculosis, abscessus and leprae infections, focusing on the applications of X-ray crystallography. I will also review our computational approaches using both statistical potentials (SDM) and machine learning methods (mCSM) for understanding mechanisms of drug resistance. These are dependent X-ray crystallographic and comparative modeling to define structures. We have demonstrated that resistance does not only arise from direct interference of the resistance mutation to drug binding but can also result allosteric mechanisms, often modifying target interactions with other proteins. This has led to new ideas about repurposing and redesigning drugs. 

Tom Blundell maintains an active laboratory as Director of Research and Professor Emeritus in the Department of Biochemistry, University of Cambridge, where he was previously Sir William Dunn Professor and Head of Department between 1996 and 2009, and Chair of School of Biological Sciences between 2003 and 2009. He has previously held teaching and research positions in the Universities of London, Sussex and Oxford.

Tom began his research career in Oxford, working with Nobel Laureate Dorothy Hodgkin on the first structure of a protein hormone, insulin. He has made major breakthroughs on the structural and computational biology and biophysics of hormones and growth factors (insulin, glucagon, NGF, HGF, FGF), receptor activation, signal transduction and DNA repair, important in cancer, tuberculosis and familial diseases. His recent work has focused on the multiprotein systems important in cell regulation and signaling. He has described complex assemblies of FGFR and Met receptor systems necessary for high signal to noise in cell signalling. He has also worked on the structural biology of the components of DNA double-strand-break repair, both Non-Homologous End Joining including DNA-PK and Homologous Recombination, focusing on Rad51 and BRCA2.

He has produced many widely used software packages for protein modelling and design, including Modeller (~10,500 citations) and Fugue (~1200 citations), and for predicting effects of mutations on protein stability and interactions (SDM & mCSM), to understand cancer & drug resistance. 

He has published ~630 research papers, including ~40 in Nature and Science, and has an H-factor of 114.. 
Tom has developed new approaches to structure-guided and fragment-based drug discovery. In 1999 he co-founded Astex Therapeutics, an oncology company that has eight drugs in clinical trials and that was sold in 2013 as Astex Pharma to Otsuka for $886 million. In parallel in the University of Cambridge he has developed structure-guided fragment-based approaches to drug discovery for difficult targets involving multiprotein systems and protein-protein interactions for the Met receptor and DNA double-strand break repair Rad51-Brca2 complexes, based on his basic research programmes. He has also been targeting ~10 Mycobacterium tuberculosis proteins as part of the Gates HIT-TB and EU-FP7 MM4TB consortia, including structural and biochemical studies of resistance mutations to first-line drugs.

Tom was a member of PM Margaret Thatcher's Advisory Council on Science & Technology (1988-1990), Founding CEO of Biotechnology and Biological Sciences Research Council, 1991-1996 (Chair 2009-2015), Chairman, Royal Commission on Environment (1998-2005), Deputy Chair of Institute of Cancer Research 2008-2015 and President of UK Science Council, 2011- 2016.