One of the key aims of the Beatson Institute is to translate our basic research for patient benefit and we are working towards this goal in two main areas; drug discovery based on biological pathways under investigation in the basic science programmes and links with clinical trials through our clinical colleagues.
Funded by Cancer Research UK and headed by Martin Drysdale, our goal is to establish an integrated, industry-standard drug discovery programme to translate basic biology research from the Beatson and other CRUK centres into medicines for the treatment of cancer.
The Drug Discovery Programme (DDP) at the Beatson has established expertise in Fragment-Based Drug Discovery (FBDD) within the Structural Biology group, integrated alongside Chemistry and Biology. State-of-the-art 600MHz NMR with cryo-cooling is used in conjunction with Surface Plasmon Resonance (SPR) as our primary fragment screening technologies, backed up by X-ray crystallography.
Finding novel compounds as starting points for optimisation is one of the major challenges in drug discovery research. Fragment-based methods have emerged in the past 10 years as an effective way to sample chemical diversity with a limited number of low molecular weight compounds. This information can be used to inform the design of new compounds with increased affinity, specificity and novelty, especially if the ternary complex structures of the fragments binding to the protein can be solved. In FBDD about 1000-1500 low molecular weight fragments are typically screened using biophysical techniques. Ideally, the experimental binding mode will be established by X-ray crystallography. Fragments are then grown to form new interactions as shown schematically below. Although fragment hits have low potency due to their small size, they form high quality interactions and can readily be optimised into potent lead molecules and ultimately clinical candidates.
Gray CH, Konczal J, Mezna M, Ismail S, Bower J, Drysdale M. A fully automated procedure for the parallel, multidimensional purification and nucleotide loading of the human GTPases KRas, Rac1 and RalB. Protein Expr Purif 2017; 132: 75-84
Konczal J, Gray CH. Streamlining workflow and automation to accelerate laboratory scale protein production. Protein Expr Purif 2017; 133: 160-9
MRCK Inhibitors UK Patent Application Number 1713319.0 filed August 18th, 2017
MRCK Inhibitors UK Patent Application Number 1713318.2 filed August 18th, 2017
Massey AJ, Stokes S, Browne H, Foloppe N, Fiumana A, Scrace S, Fallowfield M, Bedford S, Webb P, Baker L, Christie M, Drysdale MJ, Wood M.Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design. Oncotarget. 2015 Nov 3;6(34):35797-812
The Structural Biology group is central to the operation of the DDP. Responsible for Fragment-Based hit identification, this group provides expertise across protein production, NMR, SPR and X-ray crystallography. A state-of-the-art 600Mhz NMR with cryo-cooling and sample changer is used as the primary screening technology for Fragment-Based hit identification. In addition, as support for day-to-day chemistry/small molecule NMR, a 400MHz instrument with sample changer is employed.
Fundamental to Fragment-Based hit identification is the provision of orthogonal techniques to confirm the validity and suitability of hits for further work. While one aspect of this is (high concentration) biochemical screening, an orthogonal biophysical technique is also required. In our case, we use Surface Plasmon Resonance (SPR). SPR provides valuable information on both the stoichiometry as well as the kinetics of binding. These are fundamental characteristics that can critically inform for both validation as well as prioritisation of hits.
The X-ray crystallography group generates high resolution structural information to understand protein-ligand interactions in screen hits, Hits-to-Leads and Lead Optimisation compounds in order to drive design. The work is integrated with computational and medicinal chemistry to maximise the impact of the structural data generated and exploit a range of structure-based design methods. For programmes that are amenable to crystallographic studies, the Structural Biology group has the opportunity to work with the research groups and facilities of Danny Huang and Shehab Ismail to further enhance structural support.
The Chemistry group is responsible for all aspects of medicinal, synthetic, computational and analytical (purification) chemistry. In the early phase of projects, this covers the provision of chemical biology tools as well as synthesis of small compound sets for hit validation. As projects become established, the main task is resourcing Hits-to-Leads and Lead Optimisation chemistry. The Chemistry group also has significant involvement in intellectual property and identification of patent positions for composition of matter claims.
Mass directed purification is a powerful and efficient tool for the modern drug discovery laboratory. In the first instance, we have purchased a mass directed prep/analytical LCMS instrument to establish a state-of-the-art purification facility.
Computational chemistry resource are an essential part of the Chemistry group. A highly skilled computational chemist works alongside structural biology and medicinal chemistry providing key expertise in compound design, docking studies and analysis. In the cases where structural information is not obtainable, computational chemistry is involved in, for example, homology modelling and docking as well as other ligand-based design paradigms.
Justin Bower (Head of Chemistry)
The Biology group provides a key interface with the existing biology infrastructure at the Beatson as well as the wider CR-UK biology and drug discovery groups. Assay development and implementation skills are critical. Primary screening during hit validation, Hits-to-Leads and Lead Optimisation as well as cellular assay screening during these phases is established. Further, in vitro DMPK assays suitable for simple screening formats (e.g. Cytochrome P450 assays, liver microsomal turnover) are set up in order to help drive projects forward. The Biology group also has a significant role in automated cell screening in collaboration with the Beatson core.
Heather McKinnon (Head of Biology)
Launch of the Beatson Drug Discovery Programme: BBC News, 22nd September 2009