Medicinal Chemistry and Chemical Biology

Medicinal Chemistry is a recognised and long-standing strength at Newcastle. It has a strong track record of drug discovery. Newcastle discovered the first PARP inhibitors for the treatment of BRCA deficient cancer. This led to the development of rucaparib as a clinically used drug for the treatment of ovarian cancer. We have also progressed 2 other inhibitors to clinical trials. This represents an unrivalled level of success for an academic drug discovery group of this size.

Our research centres on the following themes:

• cancer drug discovery
• infectious disease drug discovery
• new approaches to drug discovery
• radiochemistry and imaging
• computational drug chemistry

We focus on rapid development of new treatments for key disease areas through active drug discovery projects and development of new technologies and methods.

The academic team work across a number of complementary themes across the Medicinal Chemistry and Chemical Biology research area.

Cancer drug discovery

Newcastle has a strong track record in the discovery of novel targeted therapies for cancer.

We are part of the Drug Discovery Programme of the Northern Institute of Cancer Research (NICR), one of four Cancer Research UK Drug Discovery Centres.

Our research aims to discover new treatments for cancers in areas of unmet clinical need. We use cutting edge drug design and synthesis techniques to develop new ways of addressing challenging protein targets, including:

• structure-based design
• fragment-based lead generation
• cutting-edge organic synthesis
• automated purification

We collaborate with colleagues in bioscience and structural biology. Our industrial partners facilitate the rapid development of lead molecules for future treatment of cancer.

Research leaders

• Celine Cano
• Ian Hardcastle
• Mike Waring

Infectious disease drug discovery

We aim to discover and develop new small molecules to treat antibiotic resistant pathogenic bacterial infections.

Many of our molecules of interest are based on natural products derived from bacteria.

We identify new antibiotic natural products using:

• synthetic organic chemistry
• synthetic biology
• molecular biology
• bioinformatics
• molecular analysis

We develop these further by understanding the mode of action of these molecules. We then apply these techniques to improve their pharmacokinetic properties for use as future drugs.

We collaborate with colleagues in microbiology, biochemistry, cell biology and analytical chemistry.

Research leader

• Michael Hall

New approaches to drug discovery

The academic team works to develop new experimental and computational approaches for drug discovery, to accelerate the discovery of the drugs of the future. These include new approaches to:

• hit identification through fragment screening and optimisation
• applications of DNA encoding in drug discovery
• computational methods for atomistic modelling of drug-protein interactions

Research leaders

• Agnieszka Bronowska
• Celine Cano
• Daniel Cole
• Ian Hardcastle
• Mike Waring

Radiochemistry and imaging

We aim to discover new molecules for imaging diseases, such as cancer and neurodegenerative diseases both in vitro and in vivo.

We use radiotracers and multi-modality imaging probes which are highly fluorescent, organelle specific and capable of carrying a radionuclide.

We develop radiochemical methods and automated production protocols using multi-step batch and flow chemistry techniques.

Our facilities include:

• the first dedicated PET radiochemistry laboratory in the region
• pre-clinical PET-CT scanners
• clinical PET-CT scanners
• clinical PET-MR scanners

This allows rapid in vivo evaluation of clinical leads and their translation through pre-clinical development to first-in-man studies.

Research leaders

• Michael Carroll
• Lee Higham
• James Knight

Computational drug discovery

We use high-performance computing in combination with experimental methods to:

• understand the mechanisms of disease
• accelerate the drug discovery process
• develop approaches to protein classes

Our research uses a wide range of techniques in our work, but our focus is on the atomistic modelling of biological molecules through:

• classical molecular dynamics
• large-scale quantum mechanical simulations
• structural bioinformatics

One focus of these activities is in new approaches to cancer and diseases of ageing.

Using computation alongside synthetic chemistry, and molecular biology, we investigate the molecular mechanisms that contribute to these age-related conditions.

Research leaders

• Agnieszka Bronowska
• Daniel Cole

Our academics working within the Medicinal Chemistry and Chemical Biology research area have strong links across the University and with both industry and academia. These include:

Cancer drug discovery

• Northern Institute for Cancer Research, as part of the drug discovery group
• Cancer Research UK, as one of four national CRUK Drug Discovery Centres
• Strategic drug discovery alliance with Astex Pharmaceuticals
• University of Leeds Astbury Centre for Structural Biology, working together on allosteric inhibitors of the Ras-activating exchange factor SOS. This project is funded by the Pancreatic Cancer Research Fund.
• member of the European Cooperation in Science and Technology (COST) Action CA17104 working with UK, EU academic and industrial partners on new diagnostic and therapeutic tools against multidrug resistant tumours

Infectious disease drug discovery

The isolation, structural characterisation and biological evaluation of new antibiotic natural products are conducted in collaboration with:

• Institute for Cell and Molecular Biosciences
• Centre for Bacterial Cell Biology
• Demuris Ltd

New approaches to drug discovery

• AstraZeneca, are focusing on innovative new approaches to cancer treatment, new methods of hit generation and chemical probe discovery.

Radiochemistry and imaging

Our research in radiotracers and multi-modality imaging probes is conducted in collaboration with:

• Centre for In Vivo Imaging
• Northern Institute for Cancer Research
• Institute of Neuroscience
• Partner in the multi-site UK Dementia Imaging Platform
• the University’s Institute of Human Genetics, working with UK, EU academic and industrial partners on 18F-tagged DNA mimics as therapeutic agents for the treatment of Duchenne Muscular Dystrophy

Computational drug discovery

• Northern Institute for Cancer Research, as part of the drug discovery group
• Astex Pharmaceuticals working on novel methods for protein-ligand binding affinity prediction. This project is funded by the EPSRC
• University of Cambridge, Theory of Condensed Matter group, working together on software tools for modelling protein and small molecule dynamics

2018

• Hill SL, Dunn M, Cano C, Harnor SJ, Hardcastle IR, Grundlingh J, Dargan PI, Wood DM, Tucker S, Bartram T, Thomas SHL. Human Toxicity Caused by Indole and Indazole Carboxylate Synthetic Cannabinoid Receptor Agonists: From Horizon Scanning to Notification. Clinical Chemistry 2018, 64(2), 346-354.
• Miller DC, Martin MP, Adhikari S, Brennan A, Endicott JA, Golding BT, Hardcastle IR, Heptinstall A, Hobson S, Jennings C, Molyneux L, Ng Y, Wedge SR, Noble MEM, Cano C. Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach. Organic and Biomolecular Chemistry 2018, 16(11), 1843-1850.
• Heptinstall AB, Adiyasa IWS, Cano C, Hardcastle IR. Recent advances in CDK inhibitors for cancer therapy. Future Medicinal Chemistry 2018, 10, epub ahead of print.
• Unterlass JE, Baslé A, Blackburn TJ, Tucker J, Turlais F, Cano C, Noble MME, Curtin NJ. Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer. Oncotarget 2018, 9, 13139-13153.
• Osher EL, Castillo F, Elumalai N, Waring MJ, Pairaudeau G, Tavassoli A. A Genetically Selected Cyclic Peptide Inhibitor of BCL6 Homodimerization. Bioorganic & Medicinal Chemistry 2018, epub ahead of print.
• Scott JS, Waring MJ. Practical application of ligand efficiency metrics in lead optimisation. Bioorganic & Medicinal Chemistry 2018, (ePub ahead of Print).
• Golding BT, Waring MJ. The consequences of ‘Brexit’ for drug discovery and development, and the regulatory implications. Expert Opinion on Drug Discovery 2018, Epub ahead of print.
• Waring MJ. The discovery of osimertinib (TAGRISSOTM): an irreversible inhibitor of activating and T790M resistance forms of the epidermal growth factor receptor tyrosine kinase. In: Fischer, J, ed. Successful Drug Discov. Wiley, 2018, pp.341. In Preparation.
• Dzeha T, Nyiro C, Kardasopoulos D, Mburu D, Mwafaida J, Hall MJ, Burgess JG. UV Resistance of bacteria isolated from the Kenyan marine cyanobacterium, Moorea Producens. MicrobiologyOpen 2018. In Press.
• Lunn S, Hribesh S, Whitfield C, Hall M, Houlton A, Brownowska A, Tuite EM, Pike AR. Duplex Healing of Selectively Thiolated Guanosine Mismatches through a Cd2+ Chemical Stimulus. ChemBioChem 2018, 19(11), 1115-1118.
• Kepplinger B, Morton S, Seistrup K, Marrs E, Hopkins A, Perry J, Strahl H, Hall M, Errington J, Allenby N. Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin. ACS Chemical Biology 2018, 13(1), 207-214.
• Basle A, Hewitt L, Koh A, Lamb HK, Thompson P, Burgess JG, Hall MJ, Hawkins AR, Murray H, Lewis RJ. Crystal structure of NucB, a biofilm-degrading endonuclease. Nucleic Acids Research 2018, 46(1), 473-484.
• Carroll B, Otten E, Manni D, Stefanatos R, Menzies F, Smith G, Jurk D, Kenneth N, Wilkinson S, Passos J, Attems J, Veal E, Teyssou E, Seilhean D, Millecamps S, Eskelinen E-L, Bronowska A, Rubinsztein DC, Sanz A, Korolchuk V. Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis. Nature Communications 2018, 9, 256.
• Imber M, Loi VV, Reznikov S, Fritsch VN, Pietrzyk-Brzezinska AJ, Prehn J, Hamilton C, Wahl MC, Bronowska AK, Antelmann H. The aldehyde dehydrogenase AldA contributes to the hypochlorite defense and is redox-controlled by protein S-bacillithiolation in Staphylococcus aureus. Redox Biology 2018, 15, 557-568.
• Allen AEA, Payne MC, Cole DJ. Harmonic Force Constants for Molecular Mechanics Force Fields via Hessian Matrix Projection. Journal of Chemical Theory and Computation 2018, 14(1), 274-281.
• Christensen PA, Bin Md Ali AH, Mashhadani ZTAW, Carroll MA, Martin PA. The Production of Ketene and C5O2 from CO2, N2and CH4 in a Non-thermal Plasma Catalysed by Earth-Abundant Elements: An In-Situ FTIR Study. Plasma Chemistry and Plasma Processing 2018, ePub ahead of print.
• Christensen P, Mashhadani Z, MdAli AHB, Carroll M, Martin P. The Production of Methane, Acetone, “Cold” CO and Oxygenated Species from Isopropyl Alcohol in a Non-Thermal Plasma: An In-Situ FTIR Study. The Journal of Physical Chemistry 2018, 122(17), 4273–4284.
• Wang G, Gibbons SK, Glueck DS, Sibbald C, Fleming JT, Higham LJ, Rheingold AL. Copper-Phosphido Intermediates in Cu(IPr)-Catalyzed Synthesis of 1-Phosphapyracenes via Tandem Alkylation/Arylation of Primary Phosphines.Organometallics 2018, 37(11), 1760-1772.

2017

• Coxon C, Anscombe E, Harnor S, Martin M, Carbain B, Golding B, Hardcastle I, Harlow L, Korolchuk S, Matheson C, Newell D, Noble M, Sivaprakasam M, Tudhope SJ, Turner D, Wang L, Wedge SR, Wong C, Griffin R, Endicott J, Cano C. Cyclin-Dependent Kinase (CDK) Inhibitors; Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines. Journal of Medicinal Chemistry 2017, 60, 1746-1767.
• Harnor SJ, Brennan A, Cano C. Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy. Medicinal Chemistry2017, 7, 172-177.
• Harnor S, Pickles J, Cano C. Modulation of the DNA-Damage Response by Inhibitors of the Phosphatidylinositol 3-Kinase Related Kinase (PIKK) Family. In: Waring M, ed. Topics in Medicinal Chemistry. Springer, 2017, pp.1-38.
• Chessari G, Howard S, Buck IM, Cons BD, Johnson CN, Holvey RS, Rees DC, StDenis JD, Tamanini E, Golding BT, Hardcastle IR, Cano CF, Miller DC, Noble MEM, Osborne JD, Peach J, Lewis A, Hirst KL, Whittaker BP, Watson DW, Mitchell DR, Griffin RJ. Preparation of isoindolinones as inhibitors of the MDM2-​p53 interaction having anticancer activity. WO/2017055859, 06/04/2017.
• Unterlass JE, Wood RJ, Basle A, Tucker J, Cano C, Noble MM, Curtin NJ. Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH). Oncotarget 2017, 8(61), 104478-104491.
• Coxon RC, Wong C, Bayliss R, Boxall K, Carr KH, Fry AM, Hardcastle IR, Matheson CJ, Newell DR, Sivaprakasam M, Thomas H, Turner D, Yeoh S, Wang LZ, Griffin RJ, Golding BT, Cano C. Structure-guided design of purine-based probes for selective Nek2 inhibition. Oncotarget 2017, 8, 19089-19124.
• Harnor S, Brennan A, Cano C. Targeting DNA-Dependent Protein Kinase for Cancer Therapy. ChemMedChem 2017, 12(12), 895-900.
• Hardcastle IR. Protein-protein interaction inhibitors. In: Bernstein, PR; Georg, GI; Keller, Th; Kobayashi, T; Lowe, JA; Meanwell, NA; Saxena, AK; Stilz, U; Supuran, CT; Zhang, A, ed. Topics in Medicinal Chemistry. Berlin, Heidelberg: Springer, 2017, pp.1-35.
• Hardcastle IR. Protein-Protein Interaction Inhibitors in Cancer. In: Chackalamannil,S;Rotella,DP;Ward,SE, ed. Comprehensive Medicinal Chemistry III. Elsevier, 2017, pp.154-201.
• McCoull W, Abrams RD, Anderson E, Blades K, Barton P, Box M, Burgess J, Byth K, Cao Q, Chuaqui C, Carbajo RJ, Cheung T, Code E, Ferguson AD, Fillery S, Fuller NO, Gangl E, Gao N, Grist M, Hargreaves D, Howard MR, Hu J, Kemmitt PD, Nelson JE, OConnell N, Prince DB, Raubo P, Rawlins PB, Robb GR, Shi J, Waring MJ, Whittaker D, Wylot M, Zhu X. Discovery of pyrazolo[1,5-a]pyrimidine B-cell lymphoma 6 (BCL6) binders and optimization to high affinity macrocyclic inhibitors.Journal of Medicinal Chemistry 2017, 60(10), 4386-4402.
• Hothersall JD, Guo D, Sarda S, Sheppard RJ, Chen H, Keur W, Waring MJ, IJzerman AP, Hill SJ, Dale IL, Rawlins PB. Structure-activity relationships of the sustained effects of adenosine A2A receptor agonists driven by slow dissociation kinetics. Molecular Pharmacology 2017, 91(1), 25-38.
• Xia L, de Vries H, Lenselink EB, Louvel J, Waring MJ, Cheng L, Pahlén S, Petersson MJ, Schell P, Olsson RI, Heitman LH, Sheppard RJ, IJzerman AP. Structure-affinity Relationships and Structure-kinetic Relationships of 1,2-Diarylimidazol-4-carboxamide Derivatives as Human Cannabinoid 1 Receptor Antagonists. Journal of Medicinal Chemistry 2017, 60(23), 9545-9564.
• England RM, Hare JI, Barnes J, Wilson J, Smith A, Strittmatter N, Kemmitt PD, Waring MJ, Barry ST, Alexander C, Ashford MB. Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers. Journal of Controlled Release 2017, 247, 73-85.
• Clarke R, Ho KL, Alsimaree AA, Waddell PG, Bogaerts J, Herrebout W, Knight J, Pal R, Penfold T, Hall MJ. Circularly Polarised Luminescence from Helically Chiral 'Confused' N,N,O,C-Boron-Chelated Dipyrromethenes (BODIPYs). ChemPhotoChem2017, 1(11), 513-517.
• Cowell J, Buck M, Essa AH, Clarke R, Vollmer W, Vollmer D, Hilkens CM, Isaacs JD, Hall MJ, Gray J. Traceless-Cleavage of Protein-Biotin Conjugates Under Biologically-Compatible Conditions. ChemBioChem 2017, 18(17), 1688-1691.
• Tyler A, Sejzi HM, Morton S, Waddell PG, Wills C, McFarlane W, Gray J, Goodfellow M, Errington J, Allenby N, Zenkin N, Hall MJ. Structural Reassignment and Absolute Stereochemistry of Madurastatin C1 (MBJ-0034) and the Related Aziridine Siderophores: Madurastatins A1, B1 and MBJ-0035. Journal of Natural Products 2017, 80(5), 1558–1562.
• Baksh A, Kepplinger B, Isah H, Probert MR, Clegg W, Wills C, Goodfellow M, Errington J, Allenby N, Hall MJ. Production of 17-O-demethyl-geldanamycin, a cytotoxic ansamycin polyketide, by Streptomyces hygroscopicus DEM20745. Natural Product Research 2017, 31(16), 1895-1900.
• Cole DJ, Janecek M, Stokes JE, Rossmann M, Faver JC, McKenzie GJ, Venkitaraman AR, Hyvönen M, Spring DR, Huggins DJ, Jorgensen WL. Computationally-Guided Optimization of Small-Molecule Inhibitors of the Aurora A Kinase – TPX2 Protein-Protein Interaction. Chemical Communications 2017, 53(67), 9372-9375.
• Joseph J, Baumann KN, Koehler P, Zuehlsdorff TJ, Cole DJ, Weber J, Bohndiek SE, Hernández-Ainsa S. Distance dependent photoacoustics revealed through DNA nanostructures. Nanoscale 2017, 9(42), 16193-16199.
• Fokas AS, Cole DJ, Hine NDM, Wells SA, Payne MC, Chin AW. Evidence of Correlated Static Disorder in the Fenna–Matthews–Olson Complex. Journal of Physical Chemistry Letters 2017, 8, 2350–2356.
• Fleming JT, Waddell PG, Probert MR, Clegg W, Higham LJ. Coinage Metal Complexes of Phosphonite Analogues of 2-Diphenylphosphino-1,1′-binaphthyl (H-MOP) and 2-Diphenylphosphino-2′-methoxy-1,1′-binaphthyl (MeO-MOP). European Journal of Inorganic Chemistry 2017, 2017(21), 2837-2844.
• Abdel-Magied AF, Majeed MH, Abelairas-Edesa MF, Ficks A, Ashour RM, Rahaman A, Clegg W, Haukka M, Higham LJ, Nordlander E. Synthesis and characterization of chiral phosphirane derivatives of [(μ-H)4Ru4(CO)12] and their application in the hydrogenation of an α,β-unsaturated carboxylic acid. Journal of Organometallic Chemistry 2017, 849-850, 71-79.
• Bowling GW, Fleming JT, Ficks A, Higham LJ. Taddol and Binol-derived chiral phosphonites in asymmetric catalysis. In:Fairlamb I; Lynam JM; J Patmore NJ; Elliott P, ed. Organometallic Chemistry. Croyden, UK: Royal Society of Chemistry, 2017, pp.93-109.

2016

• Mitcheson DF, Bottrill AR, Carr K, Coxon CR, Cano C, Golding BT, Griffin RJ, Fry AM, Doerig C, Bayliss R, Tobin AB. A new tool for the chemical genetic investigation of the Plasmodium falciparum Pfnek-2 NIMA-related kinase. Malaria Journal 2016, 15, 535.
• Beale G, Haagensen E, Thomas H, Wang LZ, Revill C, Payne S, Golding BT, Hardcastle IR, Newell DR, Griffin RJ, Cano C. Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo anti-tumour activity in colorectal cancer.British Journal of Cancer 2016, 115, 682-690.
• Zaytsev AV, Pickles JE, Harnor SJ, Henderson AP, Alyasiri M, Waddell PG, Cano C, Griffin RJ, Golding BT. Concise syntheses of bridged morpholines. RSC Advances 2016, 6(59), 53955-53957.
• Reuillon T, Alhasan SF, Beale GS, Bertoli A, Brennan A, Cano C, Reeves HL, Newell DR, Golding BT, Miller DC, Griffin RJ. Design and synthesis of biphenyl and biphenyl ether inhibitors of sulfatases. Chemical Science 2016, 7(4), 2821-2826.
• Myers SM, Bawn RH, Bisset LC, Blackburn TJ, Cottyn B, Molyneux L, Wong AC, Cano C, Clegg W, Harrington RW, Leung H, Rigoreau L, Vidot S, Golding BT, Griffin RJ, Hammonds T, Newell DR, Hardcastle IR. High-throughput screening and hit validation of extracellular-related kinase 5 (ERK5) inhibitors. ACS Combinatorial Science 2016, 18(8), 444-455.
• Reuillon T, Miller D, Myers S, Molyneux L, Cano C, Hardcastle I, Griffin R, Rigoreau L, Golding B, Noble M. Pyrrolcarboxamide Derivatives for the Inhibition of ERK5. WO/2016/042341, 24/03/2016.
• Cortese D, Konstantin C, Guglielmo S, Wang LZ, Golding BT, Cano C, Fruttero R. Synthesis and Biological Evaluation of N2-Substituted 2,4-Diamino-6-cyclohexylmethoxy-5-nitrosopyrimidines and Related 5-Cyano-NNO-azoxy Derivatives as Cyclin-Dependent Kinase 2 (CDK2) Inhibitors. ChemMedChem 2016, 11(6), 1705-1708.
• Drummond CJ, Esfandiari A, Liu J, Lu X, Hutton C, Jackson J, Bennaceur K, Xu Q, Makimanejavali AR, Bello FD, Piergentili A, Newell DR, Hardcastle IR, Griffin RJ, Lunec J. TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation. Oncotarget 2016, 7(29), 46203-46218.
• Rhyasen GW, Hattersley M, Yao Y, Dulak A, Wang W, Petteruti P, Dale I, Boiko S, Cheung T, Zhang J, Wen S, Castriotta L, Lawson D, Collins M, Bao L, Ahdesmaki MJ, Walker G, O'Connor G, Yeh T, Rabow AA, Dry J, Reimer C, Lyne P, Mills GB, Fawell S, Waring MJ, Zinda M, Clark E, Chen H. AZD5153: a novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies. Molecular Cancer Therapeutics 2016, 15(11), 2563-2574.
• England RM, Hare JI, Kemmitt PD, Treacher K, Waring MJ, Barry ST, Alexander C, Ashford M. Enhanced cytocompatibility and functional group content of poly(L-lysine) dendrimers by grafting with poly(oxazolines). Polymer Chemistry 2016, 7(28), 4609-4617.
• Bradbury RH, Callis R, Carr GR, Chen H, Clark E, Feron L, Glossop S, Graham MA, Hattersley M, Jones C, Lamont SG, Ouvry G, Patel A, Patel J, Rabow AA, Roberts CA, Stokes S, Stratton N, Walker GE, Ward L, Whalley D, Whittaker D, Wrigley G, Waring MJ. Optimisation of a series of bivalent triazolopyridazine based bromodomain and extraterminal inhibitors: the discovery of (3R)-4-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153). Journal of Medicinal Chemistry 2016, 59(17), 7801-7817.
• Waring MJ, Chen H, Rabow AA, Walker G, Bobby R, Boiko S, Bradbury RH, Callis R, Clark E, Dale E, Daniels DL, Dulak A, Flavell L, Holdgate G, Jowitt TA, Kikhney A, McAlister M, Mendez J, Ogg D, Patel J, Petteruti P, Robb GR, Robers MB, Saif S, Stratton N, Svergun DI, Wang W, Whittaker D, Wilson DM, Yao Y. Potent and selective bivalent inhibitors of BET bromodomains. Nature Chemical Biology 2016, 12, 1097-1104.
• Bradbury RH, Rabow AA, Waring MJ, McCabe JF, Glossop SC, Mahmood A, Cotter ZA. Preparation of triazolopyridazine derivatives for use as antiproliferative agents. 04/02/2016.
• Alnoman RB, Rihn S, OConnor DC, Black FA, Costello B, Waddell PG, Clegg W, Peacock RD, Herrebout W, Knight JG, Hall MJ. Circularly Polarized Luminescence from Helically Chiral N,N,O,O-Boron Chelated Dipyrromethenes. Chemistry - A European Journal 2016, 22(1), 93-96.
• Abualnaja M, Waddell PG, Clegg W, Hall MJ. Synthesis of pentacyclic pyrrolo[3,4-a]carbazole-1,3(2H)-diones via an intermolecular Diels-Alder, intramolecular carbonyl-ene reaction strategy. Tetrahedron 2016, 72(38), 5798-5806.
• Cole DJ, Hine NDM. Applications of Large-Scale Density Functional Theory in Biology. Journal of Physics: Condensed Matter 2016, 28(39), 393001.
• Cole DJ, Vilseck JZ, Tirado-Rives J, Payne MC, Jorgensen WL. Biomolecular Force Field Parameterization via Atoms-in-Molecular Electron Density Partitioning. Journal of Chemical Theory and Computation 2016, 12(5), 2312-2323.
• Morgan SE, Cole DJ, Chin AW. Nonlinear network model analysis of vibrational energy transfer and localisation in the Fenna-Matthews-Olson complex. Scientific Reports 2016, 6, 36703.
• Fokas AS, Cole DJ, Ahnert SE, Chin AW. Residue Geometry Networks: A Rigidity-Based Approach to the Amino Acid Network and Evolutionary Rate Analysis. Scientific Reports 2016, 6, 33213.
• Eze V, Abegao FJR, Carroll M, Harvey A, Wilson K. Development of Heterogeneous Catalysts for Valorisation of CO2 and Crude Glycerol. In: Process Intensification Network 24. 2016, Newcastle, United Kingdom.
• Eze VC, Abegão FJR, Harvey AP, Carroll M. Heterogeneous Catalytic Processes for Valorisation of Crude Glycerol from Biodiesel Productions. In: 2nd International Conference on Green Chemistry and Sustainable Engineering. 2016, Rome, Italy.
• Doherty S, Knight JG, Carroll MA, Clemmet AR, Ellison JR, Backhouse T, Holmes N, Bourne RA. Selective and Highly Efficient Hydrogen Peroxide-Mediated Oxidation of Sulfides in Batch and Continuous Flow using Styrene-Based Polymer Immobilised Ionic Liquid Phase Supported Peroxotungstates. RSC Advances 2016, 6, 73118-73131.
• Fleming JT, Wills C, Waddell PG, Harrington RW, Higham LJ. A comparison of MOP-phosphonite ligands and their applications in Rh(I)- and Pd(II)-catalysed asymmetric transformations. Dalton Transactions 2016, 45(39), 15660-15670.
• Nigam S, Burke BP, Davies LH, Domarkas J, Wallis JF, Waddell PG, Waby JS, Benoit DM, Seymour AM, Cawthorne C, Higham LJ, Archibald SJ. Structurally optimised BODIPY derivatives for imaging of mitochondrial dysfunction in cancer and heart cells. Chemical Communications 2016, 52(44), 7114-7117.
• Davies LH, Wallis JF, Harrington RW, Waddell PG, Higham LJ. Air-stable fluorescent primary phosphine complexes of molybdenum and tungsten. Journal of Coordination Chemistry 2016, 69(11-13), 2069-2080.
• Walsh JPS, Bowling G, Ariciu A-M, Jailani NFM, Chilton NF, Waddell PG, Collison D, Tuna F, Higham LJ. Evidence of Slow Magnetic Relaxation in Co(AcO)2(py)2(H2O)2. Magnetochemistry 2016, 2(2), 23.
• Fleming JT, Ficks A, Waddell PG, Harrington RW, Higham LJ. The design of second generation MOP-phosphonites: efficient chiral hydrosilylation of functionalised styrenes. Dalton Transactions 2016, 45(5), 1886-1890.
• Bange CA, Ghebreab MB, Ficks A, Mucha NT, Higham LJ, Waterman R. Zirconium-catalyzed intermolecular hydrophosphination using a chiral, air-stable primary phosphine. Dalton Transactions 2016, 45(5), 1863-1867.

2015

• Anscombe E, Meschini E, Mora-Vidal R, Martin MP, Staunton D, Geitmann M, Danielson UH, Stanley WA, Wang LZ, Reuillon T, Golding BT, Cano C, Newell DR, Noble MEM, Wedge SR, Endicott JA, Griffin RJ. Identification and characterization of an irreversible inhibitor of CDK2. Chemistry & Biology 2015, 22(9), 1159-1164.
• Unterlass JE, Aljufri N, Bex S, Cano C, Noble MEM, Curtin NJ. Towards structure-based drug design of 3-phosphoglycerate dehydrogenase inhibitors. In: AACR 106th Annual Meeting 2015. 2015, Philadelphia, PA, USA: American Association for Cancer Research.
• Rasheed OK, Hardcastle IR, Raftery J, Quayle P. Aryne generation vs. Truce-Smiles and fries rearrangements during the Kobayashi fragmentation reaction: a new bi-aryl synthesis. Organic & Biomolecular Chemistry 2015, 13(29), 8048-8052.
• Zaytsev A, Dodd B, Magnani M, Ghiron C, Golding BT, Griffin RJ, Liu J, Lu X, Micco I, Newell DR, Padova A, Robertson G, Lunec J, Hardcastle IR. Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein-Protein Interaction by a Scaffold-Hopping Approach. Chemical Biology and Drug Discovery 2015, 86(2), 180-189.
• Zhang B, Golding BT, Hardcastle IR. Small-molecule MDM2-p53 inhibitors: recent advances. Future Medicinal Chemistry2015, 7(5), 631-645.
• Waring MJ, Bennett SNL, Campbell L, Hallam S, Martin NG, Tickner C. A safe and scalable synthesis of 2-hydroxy-3-alkoxypropionates by epoxide ring opening. Tetrahedron Letters 2015, 56(34), 4904-4907.
• Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, Pairaudeau G, Pennie W, Pickett SD, Wang J, Wallace O, Weir A. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nature Reviews Drug Discovery 2015, 14, 475-486.
• Waring MJ, Leach AG, Miller DC. Challenges in the Medicinal Chemical Optimization of Binding Kinetics. In: Thermodynamics and Kinetics of Drug Binding. Wiley Blackwell, 2015, pp.191-210.
• Waring MJ, Baker DJ, Bennett SNL, Dossetter AG, Fenwick M, Garcia R, Georgsson J, Groombridge SD, Loxham S, MacFaul PA, Maskill KG, Morgan D, Morrell J, Pointon H, Robb GR, Smith DM, Stokes S, Wilkinson G. Discovery of a series of 2-(pyridinyl)pyrimidines as potent antagonists of GPR40. MedChemComm 2015, (6), 1024-1029.
• Raubo P, Andrews DM, McKelvie JC, Robb GR, Smith JM, Swarbrick ME, Waring MJ. Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα). Bioorganic & Medicinal Chemistry Letters 2015, 25(16), 3189-3193.
• Cowell J, Abualnaja M, Morton S, Linder R, Buckingham F, Waddell PG, Probert MR, Hall MJ. Diastereoselective synthesis of functionalised carbazoles via a sequential Diels-Alder/ene reaction strategy. RSC Advances 2015, 5(21), 16125-16152.
• Cowell J, Harrington RW, Probert MR, Hall MJ. Enantioselective synthesis of functionalised tetrahydrocarbazoles via an organocatalysed Diels-Alder/ene reaction strategy. Tetrahedron: Asymmetry 2015, 26(20), 1189-1196.
• Essa AH, Lerrick RI, Çiftçi E, Harrington RW, Waddell PG, Clegg W, Hall MJ. Grignard-mediated reduction of 2,2,2-trichloro-1-arylethanones. Organic & Biomolecular Chemistry 2015, 13(20), 5793-5803.
• Peralta D, Bronowska AK, Morgan B, Dóka É, VanLaer K, Nagy P, Gräter F, Dick TP. A proton relay enhances H2O2 sensitivity of GAPDH to facilitate metabolic adaptation. Nature Chemical Biology 2015, 11, 156-163.
• Zhou J, Bronowska AK, LeCoq J, Lietha D, Gräter F. Allosteric regulation of focal adhesion kinase by PIP₂ and ATP.Biophysical Journal 2015, 108(3), 698-705.
• Aponte-Santamaría C, Huck V, Posch S, Bronowska AK, Grässle S, Brehm MA, Obser T, Schneppenheim R, Hinterdorfer P, Schneider SW, Baldauf C, Gräter F. Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions. Biophysical Journal 2015, 108(9), 2312-2321.
• Zhou J, Aponte-Santamaria C, Sturm S, Bullerjahn JT, Bronowska A, Graeter F. Mechanism of Focal Adhesion Kinase Mechanosensing. PLoS Computational Biology 2015, 11(11), e1004593.
• White SJ, Johnson SD, Sellick MA, Bronowska AK, Stockley PG, Wälti C. The influence of two-dimensional organization on peptide conformation. Angewandte Chemie International Edition 2015, 54(3), 974-978.
• Cole DJ, Tirado-Rives J, Jorgensen WL. Molecular Dynamics and Monte Carlo Simulations for Protein-Ligand Binding and Inhibitor Design. Biochimica et Biophysica Acta (BBA) General Subjects 2015, 1850(5), 966-971.
• Doherty S, Knight JG, Carroll MA, Ellison JR, Hobson SJ, Stevens S, Hardacre C, Goodrich P. Efficient and selective hydrogen peroxide-mediated oxidation of sulfides in batch and segmented and continuous flow using a peroxometalate-based polymer immobilised ionic liquid phase catalyst. Green Chemistry 2015, 17(3), 1559-1571.
• Fleming JT, Higham LJ. Primary Phosphine Chemistry. Coordination Chemistry Reviews 2015, 297-298, 127-145.
• Fey N, Papadouli S, Pringle PG, Ficks A, Fleming JT, Higham LJ, Wallis JF, Carmichael D, Mézailles N, Müller C. Setting P-Donor Ligands into Context: An Application of the Ligand Knowledge Base (LKB) Approach. Phosphorus, Sulfur, and Silicon and the Related Elements 2015, 190(5-6), 706-714.

2014

• Carbain B, Paterson DJ, Anscombe E, Campbell AJ, Cano C, Echalier A, Endicott JA, Golding BT, Haggerty K, Hardcastle IR, Jewsbury PJ, Newell DR, Noble MEM, Roche C, Wang LZ, Griffin RJ. 8-Substituted O-6-Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode. Journal of Medicinal Chemistry 2014, 57(1), 56-70.
• Lebraud H, Golding BT, Meschini E, Cano C, Anscombe E, Wang LZ, Endicott JA, Noble MEM, Newell DR, Griffin RJ. Anticancer agents targeted against cyclin-dependent kinase 2 (CDK2): Structure-based design of irreversible and reversible inhibitors. In: 247th ACS National Meeting and Exposition. 2014, Dallas, Texas: American Chemical Society.
• Myers S, Martin N, Bawn R, Blackburn T, Barrett L, Reuillon T, Golding B, Griffin R, Hammonds T, Hardcastle I, Leung H, Newell D, Rigoreau L, Wong A, Cano C. Development of extracellular signal-regulated kinase 5 (ERK5) inhibitors for anti-cancer therapy. In: 26th EORTC – NCI – AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014, Barcelona, Spain: Elsevier.
• Mould E, Berry P, Jamieson D, Hill C, Cano C, Tan N, Elliott S, Durkacz B, Newell D, Willmore E. Identification of dual DNA-PK MDR1 inhibitors for the potentiation of cytotoxic drug activity. Biochemical Pharmacology 2014, 88(1), 58-65.
• Lebraud H, Coxon CR, Archard VS, Bawn CM, Carbain B, Matheson CJ, Turner DM, Cano C, Griffin RJ, Hardcastle IR, Baisch U, Harrington RW, Golding BT. Model system for irreversible inhibition of Nek2: thiol addition to ethynylpurines and related substituted heterocycles. Organic & Biomolecular Chemistry 2014, 12, 141-148.
• Tudhope S, Zhao Y, Wittner A, Wilmore E, Bertoli A, Adhikari S, Harnor SJ, Del Bello F, Piergentili A, Lunec J, Hardcastle IR, Griffin RJ, Golding BR, Cano C, Newell DR, Wedge SR. Profiling inhibitors of MDM2: p53 and MDMX: p53 in relation to MDMX protein levels. In: AACR Annual Meeting 2014. 2014, San Diego, CA: American Association for Cancer Research.
• Harnor SJ, Rennison T, Galler M, Cano C, Griffin RJ, Newell DR, Golding BT. Synthesis of 3 '-deoxy-3'-fluorothymidine (FLT) 5 '-O-glucuronide: a reference standard for imaging studies with [18F]FLT. MedChemComm 2014, 5(7), 984-988.
• Carbain B, Coxon CR, Lebraud H, Elliott KJ, Matheson CJ, Meschini E, Roberts AR, Turner DM, Wong C, Cano C, Griffin RJ, Hardcastle IR, Golding BT. Trifluoroacetic Acid in 2,2,2-Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines. Chemistry: A European Journal 2014, 20(8), 2311-2317.
• Bertoli A, Adhikari S, Harnor SJ, Zhao Y, Lunec J, Wedge SR, Tudhope S, Wittner A, Golding BT, Hardcastle IR, Cano C, Newell DR, Griffin RJ. Validation studies with small-molecule modulators of the MDM2/MDMX-p53 binding interaction. In: 247th ACS National Meeting and Exposition. 2014, Dallas, TX, USA: American Chemical Society.
• Anil B, Blackburn E, Blackburn T, Cully S, Liu J, Drummond CJ, Endicott JA, Golding BT, Griffin RJ, Haggerty K, Lunec J, Newell DR, Revill CH, Riedinger C, Watson AF, Xu Q, Zhao Y, Hardcastle IR, Noble MEM. An X-ray crystal structure-based understanding of the inhibition of the MDM2-p53 protein-protein interaction by isoindolinones. In: 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014, Barcelona, Spain: Elsevier.
• Cinatl J, Speidel D, Hardcastle I, Michelis M. Resistance acquisition to MDM2 inhibitors. Biochemical Society Transactions2014, 42(4), 752–757.
• Hardcastle IR. Targeting the MDM2-p53 protein-protein interaction: Design, discovery, and development of novel anticancer agents. In: Neidle, S, ed. Cancer drug design and discovery. Elsevier, Academic Press, 2014, pp.391-426.
• Carbain B, Coxon CR, Lebraud H, Elliott KJ, Matheson CJ, Meschini E, Roberts AR, Turner DM, Wong C, Cano C, Griffin RJ, Hardcastle IR, Golding BT. Trifluoroacetic Acid in 2,2,2-Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines. Chemistry: A European Journal 2014, 20(8), 2311-2317.
• Gill DM, McLay N, Waring MJ, Wilkinson CT, Sweeney JB. An Improved Method for Difluorocyclopropanation of Alkenes.Synlett 2014, 25(12), 1756-1756.
• Finlay MRV, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, Chorley C, Colclough N, Cross DAE, Currie GS, Grist M, Hassall L, Hill GB, James D, James M, Kemmitt P, Klinowska T, Lamont G, Lamont SG, Martin N, McFarland HL, Mellor MJ, Orme JP, Perkins D, Perkins P, Richmond G, Smith P, Ward RA, Waring MJ, Whittaker D, Wells S, Wrigley GL. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. Journal of Medicinal Chemistry 2014, 57(20), 8249-8267.
• Waring MJ, Andrews DM, Faulder PF, Flemington V, McKelvie JC, Maman S, Preston M, Raubo P, Robb GR, Roberts K, Rowlinson R, Smith JM, Swarbrick ME, Treines I, Winter JG, Wood RJ. Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not β- inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation. Chemical Communications 2014, 50(40), 5388-5390.
• Cumming JG, Finlay MRV, Giordanetto F, Hemmerling M, Lister T, Sanganee H, Waring MJ. The challenges of increasing drug discovery productivity. Future Medicinal Chemistry 2014, 6(5), 515-527.
• Oxley A, Berry P, Taylor GA, Cowell J, Hall MJ, Hesketh J, Lietz G, Boddy AV. An LC/MS/MS method for stable isotope dilution studies of β-carotene bioavailability, bioconversion and vitamin A status in humans. Journal of Lipid Research2014, 55(2), 319-328.
• Lerrick RI, Winstanley TPL, Haggerty K, Wills C, Clegg W, Harrington RW, Bultinck P, Herrebout W, Benniston AC, Hall MJ. Axially Chiral BODIPYs. Chemical Communications 2014, 50(36), 4714-4716.
• Goñi GM, Epifano C, Boskovic J, Camacho-Artacho M, Zhou J, Bronowska AK, Martín MT, Eck MJ, Kremer L, Gräter F, Gervasio FL, Perez-Moreno M, Lietha D. Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proceedings of the National Academy of Sciences of the United States of America 2014, 111(31), E3177-E3186.
• Fokas AS, Cole DJ, Chin AW. Constrained geometric dynamics of the Fenna–Matthews–Olson complex: the role of correlated motion in reducing uncertainty in excitation energy transfer. Photosynthesis Research 2014, 122(3), 275-292.
• Belfield WJ, Cole DJ, Martin IL, Payne MC, Chau P-L. Constrained geometric simulation of the nicotinic acetylcholine receptor. Journal of Molecular Graphics and Modelling 2014, 52, 1-10.
• Cole DJ, Tirado-Rives J, Jorgensen WL. Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering. Journal of Chemical Theory and Computation 2014, 10(2), 565-571.
• Lee LP, Gabaldon Limas N, Cole DJ, Payne MC, Skylaris C-K, Manz TA. Expanding the Scope of Density Derived Electrostatic and Chemical Charge Partitioning to Thousands of Atoms. Journal of Chemical Theory and Computation2014, 10(12), 5377-5390.
• Kozuska JL, Paulsen IM, Belfield WJ, Martin IL, Cole DJ, Holt A, Dunn SMJ. Impact of Intracellular Domain Flexibility upon Properties of Activated Human 5-HT3 Receptors. British Journal of Pharmacology 2014, 171(7), 1617-1628.
• Lever G, Cole DJ, Lonsdale R, Ranaghan KE, Wales DJ, Mulholland AJ, Skylaris C-K, Payne MC. Large-Scale Density Functional Theory Transition State Searching in Enzymes. Journal of Physical Chemistry Letters 2014, 5(21), 3614-3619.
• Weber C, Cole DJ, O'Regan DD, Payne MC. Renormalization of Myoglobin-ligand Binding Energetics by Quantum Many-body Effects. Proceedings of the National Academy of Sciences of the United States of America 2014, 111(16), 5790-5795.
• Dixon LI, Carroll MA, Ellames GJ, Gregson T. Synthesis of Alkynyliodonium Salts: Preparation of Phenyl(phenylethynyl)iodonium Trifluoroacetate. Organic Syntheses 2014, 91, 60-71.
• Davies LH, Kasten BB, Benny PD, Arrowsmith RL, Ge H, Pascu SI, Botchway SW, Clegg W, Harrington RW, Higham LJ. Re and 99mTc complexes of BodP3 – multi-modality imaging probes. Chemical Communications 2014, 50(98), 15503-15505.
• Ficks A, Clegg W, Harrington RW, Higham LJ. Air-Stable Chiral Primary Phosphines: A Gateway to MOP Ligands with Previously Inaccessible Stereoelectronic Profiles. Organometallics 2014, 33(22), 6319-6329.
• Davies LH, Harrington RW, Clegg W, Higham LJ. BR2BodPR2: highly fluorescent alternatives to PPh3 and PhPCy2. Dalton Transactions 2014, 43(36), 13485-13499.
• Davies LH, Wallis JF, Probert MR, Higham LJ. Efficient Multigram Syntheses of Air-Stable, Fluorescent Primary Phosphines via Palladium-Catalyzed Phosphonylation of Aryl Bromides. Synthesis 2014, 46(19), 2622-2626.
• Davies LH, Higham LJ. Air-Stable, Fluorescent Primary Phosphines. In: Fairlamb,I.J.S;Lynam,J.M, ed. Organometallic Chemistry. Royal Society of Chemistry, 2014, pp.51-71.