Drug Discovery Unit
Cancer Research UK currently has more than 30 agents in pre-clinical and clinical development, two drugs in phase III trials and five drugs already on the market being used to treat patients. Led by Justin Bower and Heather McKinnon, the Drug Discovery Unit (DDU) is an integrated, industry-standard drug discovery group translating basic biology research from the Beatson Institute and other CRUK centres into medicines for the treatment of cancer.
One of the key aims of the Beatson Institute is to translate cutting edge cancer biology 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 the Glasgow Cancer Centre and ECMC clinical infrastructure. We have chosen to pursue research that is fundamental to the course of disease in patients, even if the targets we identify are highly challenging from a druggability perspective. This "high-risk / high reward" approach to translational research is at the core of Cancer Research UK's approach to tackling critical mechanisms of cancer survival with the potential for game changing treatments for patients.
On tough targets fragment-based approaches have shown to deliver more starting points (e.g. hits) compared with more canonical hit-finding techniques. We have profound expertise in Fragment-Based Drug Discovery (FBDD) within the Structural Biology group, integrated alongside Chemistry and Biology. Nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR) are used as our primary fragment screening technologies in combination with X-ray crystallography and isothermal titration calorimetry (ITC) for further characterisation including thermodynamic properties. Utilising these methods we are targeting a wide range of challenging oncology targets including protein-protein and protein-DNA/RNA interactions.
Hayatigolkhatmi K, Padroni G, Su W, Fang L, Gomez-Castaneda E, Hsieh YC, Jackson L, Pellicano F, Burley GA, Jorgensen HG. An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells. Bioorganic & medicinal chemistry letters. 2019;10.1016/j.bmcl.2019.07.049.
Konczal J, Bower J, Gray CH. Re-introducing non-optimal synonymous codons into codon-optimized constructs enhances soluble recovery of recombinant proteins from Escherichia coli. PloS one 2019; 14: e0215892.
Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents. Francis S, Croft D, Schuttelkopf AW, Parry C, Pugliese A, Cameron K, Claydon S, Drysdale M, Gardner C, Gohlke A, Goodwin G, Gray CH, Konczal J, McDonald L, Mezna M, Pannifer A, Paul NR, Machesky L, McKinnon H, Bower J. Bioorg Med Chem Lett. 2019; 29: 1023-9.
A novel small molecule inhibitor of MRCK prevents radiation driven invasion in glioblastoma. Joanna L. Birch, Karen Strathdee, Lesley Gilmore, Antoine Vallatos, Laura McDonald, Ariadni Kouzeli, Abdulrahman Hussain Qaisi, Justin Bower, Daniel Croft, Diane Crighton, Kathryn Gill, Christopher Gray, Jennifer Konczal, Duncan McArthur, Patricia McConnell, Mokdad Mezna, Alexander W Schuttelkopf, Mairi Sime, William Holmes, Heather McKinnon, Martin Drysdale, Mike F. Olson, Anthony J Chalmers. Cancer Res. 2018. doi: 10.1158/0008-5472.CAN-18-1697. [Epub ahead of print]
Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer. Mathieu Unbekandt, Simone Belshaw, Justin Bower, Maeve Clarke, Jacqueline Cordes, Diane Crighton, Daniel Croft, Martin Drysdale, Mathew Garnett, Kathryn Gill, Christopher Gray, David Greenlaugh, James Hall, Jennifer Konczal, Sergio Lilla, Duncan McArthur, Patricia McConnell, Laura McDonald, Lynn McGarry, Heather McKinnon, Carol McMenemy, Mokdad Mezna, Nicolas Morrice, June Munro, Gregory Naylor, Nicola Rath, Alexander Schüttelkopf, Mairi Sime and Michael Olson. Cancer Research, 2017 (accepted for publication)
Accepting from the best donor; analysis of long-lifetime donor fluorescent protein pairings to optimise dynamic FLIM-based FRET experiments. Martin KJ, McGhee EJ, Schwarz JP, Drysdale M, Brachmann SM, Stucke V, Sansom OJ, Anderson KI. PLoS One. 2018 Jan 2;13
Streamlining workflow and automation to accelerate laboratory scale protein production. Konczal J, Gray CH. Protein Expr Purif. 2017 May; 133:160-169
A fully automated procedure for the parallel, multidimensional purification and nucleotide loading of the human GTPases KRas, Rac1 and RalB. Gray CH, Konczal J, Mezna M, Ismail S, Bower J, Drysdale M. Protein Expr Purif. 2017 Apr; 132:75-84
Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Using Artificial Neural Networks. Bilsland AE, Pugliese A, Liu Y, Revie J, Burns S, McCormick C, Cairney CJ, Bower J, Drysdale M, Narita M, Sadaie M, Keith WN. Neoplasia. 2015 Sep 17(9):704-715
Strategies for Fragment Library Design. J Bower, A Pugliese, M Drysdale - Fragment-based Drug Discovery: Lessons and Outlook, Wiley 2015
A novel small-molecule MRCK inhibitor blocks cancer cell invasion. Cell Commun Signal. Unbekandt M, Croft DR, Crighton D, Mezna M, McArthur D, McConnell P, Schüttelkopf AW, Belshaw S, Pannifer A, Sime M, Bower J, Drysdale M, Olson MF. 2014 Oct 5 12:54
Fragment-based hit identification: thinking in 3D. Morley AD, Pugliese A, Birchall K, Bower J, Brennan P, Brown N, Chapman T, Drysdale M, Gilbert IH, Hoelder S, Jordan A, Ley SV, Merritt A, Miller D, Swarbrick ME, Wyatt PG. Drug Discov Today. 2013 Dec 18(23-24):1221-7
Using fragment-based technologies to target protein-protein interactions. Bower JF, Pannifer A.
Curr Pharm Des. 2012 18(30):4685-96
MRCK Inhibitors UK Patent Application Number 1713319.0 filed August 18th, 2017
MRCK Inhibitors UK Patent Application Number 1713318.2 filed August 18th, 2017
Probing the ability of a novel MRCK inhibitor, BDP-0009066, to prolong survival in a pre-clinical model of Glioblastoma. Anthony Chalmers. Cancer Research Technology. 2018 - 2019