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.
Knight JRP, Alexandrou C, Skalka GL, Vlahov N, Pennel K, Officer L, Teodosio A, Kanellos G, Gay DM, May-Wilson S, Smith EM, Najumudeen AK, Gilroy K, Ridgway RA, Flanagan DJ, Smith RCL, McDonald L, MacKay C, Cheasty A, McArthur K, Stanway E, Leach JDG, Jackstadt R, Waldron JA, Campbell AD, Vlachogiannis G, Valeri N, Haigis KM, Sonenberg N, Proud CG, Jones NP, Swarbrick ME, McKinnon HJ, Faller WJ, Le Quesne J, Edwards J, Willis AE, Bushell M, Sansom OJ. MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression. Cancer discovery. 2020:CD-20-0652.
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. 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. Bioorg Med Chem Lett. 2019; 29: 1023-9.
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; 29: 2622-2625
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.
Birch JL, Strathdee K, Gilmore L, Vallatos A, McDonald L, Kouzeli A, Qaisi AH, Bower J, Croft D, Crighton D, Gill K, Gray C, Konczal J, McArthur D, McConnell P, Mezna M, Schuttelkopf AW, Sime M, Holmes W, McKinnon H, Drysdale M, Olson MF, Chalmers AJ. A novel small molecule inhibitor of MRCK prevents radiation driven invasion in glioblastoma.Cancer Res. 2018; 78: 6509-6522
Unbekandt M, Belshaw S, Bower J, Clarke M, Cordes J, Crighton D, Croft D, Drysdale M, Garnett M, Gill K, Gray C, Greenlaugh D, Hall J, Konczal J, Lilla S, McArthur D, McConnell P, McDonald L, McGarry L, McKinnon H, McMenemy C, Mezna M, Morrice N, Munro J, Naylor G, Rath N, Schüttelkopf A, Sime M and Olson M. Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer. Cancer Res. 2018; 78: 2096-2114
Martin KJ, McGhee EJ, Schwarz JP, Drysdale M, Brachmann SM, Stucke V, Sansom OJ, Anderson KI. Accepting from the best donor; analysis of long-lifetime donor fluorescent protein pairings to optimise dynamic FLIM-based FRET experiments. PLoS One. 2018; 13
Konczal J, Gray CH. Streamlining workflow and automation to accelerate laboratory scale protein production. Protein Expr Purif. 2017; 133:160-169
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
Bilsland AE, Pugliese A, Liu Y, Revie J, Burns S, McCormick C, Cairney CJ, Bower J, Drysdale M, Narita M, Sadaie M, Keith WN. Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Using Artificial Neural Networks. Neoplasia. 2015; 17:704-715
Bower J, Pugliese A, Drysdale M Strategies for Fragment Library Design. - Fragment-based Drug Discovery: Lessons and Outlook, Wiley 2016
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. A novel small-molecule MRCK inhibitor blocks cancer cell invasion. Cell Commun Signal. 2014; 12:54
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. Fragment-based hit identification: thinking in 3D Drug Discov Today. 2013; 18:1221-7
Bower JF, Pannifer A. Using fragment-based technologies to target protein-protein interactions. Curr Pharm Des. 2012; 18: 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