Structural biology and drug discovery: Fighting the emergence of resistance in cancer and mycobacterial infections
This is part of our Distinguished Lecture series, which is aimed at a general audience. The event will be preceded by tea and cakes in the Queen's Building, from 17.00.
Abstract
The emergence of drug resistance is a challenge that is facing drug discovery in both cancer and infectious disease. Next generation sequencing has shown that mechanisms of resistance to the same drug in different tumours or pathogens can vary extensively. The challenge will be one in personalised or precision medicine.
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 - Astex, the company I cofounded, has a breast cancer on the market and eight in clinical trials. The method is effective not only for classical enzyme targets but also for less “druggable” targets such as protein-protein interfaces. Our approach involves a fast initial screening using biophysical techniques 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 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 (protein-protein interfaces) and in Mycobacterium Tuberculosis and Mycobacterium Abscessus infections.
I will also review our new computational approaches using both statistical potentials and machine learning methods for understanding mechanisms of resistance. These 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. These lead to new ideas about repurposing and redesigning drugs and even in reclassifying patients in clinical trials.
Bio
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 ~600 research papers, including ~40 in Nature and Science, and has an H-factor of 109.
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.
