Northern Institute for Cancer Research

Medicinal Chemistry

Medicinal Chemistry

About

We select targets, discover chemical leads and optimise them towards drug molecules. We work in close collaboration with colleagues in bioscience and structural biology.

Research Leaders

Mike Waring
Celine Cano
Ian Hardcastle

Our research programme

Selecting targets based on their novelty and the strength of biological and clinical hypothesis is more chemically challenging than traditional approaches. 

We use our expertise in drug design and chemical synthesis to tackle these challenges. We're guided by structural information and computational analysis. 

We use modern hit finding approaches with an emphasis on fragment based lead generation. We also use high-throughput screening and rational ligand design to generate hit molecules. 

These hits are then optimised using structure and property based design. This generates compounds for target validation and for progression towards clinical candidates.

Enabling Science

In addition to our core activities in drug discovery, we also develop new enabling methodology.  This aims to improve the way we do medicinal chemistry. 

This includes developing:

  • new approaches to compound screening and optimisation
  • chemical biology based methods for target selection and validation
  • new computational methods for modelling protein–ligand interactions

Facilities

Our laboratories are in the Bedson building. We've excellent facilities for contemporary medicinal chemistry. 

Our synthetic chemistry laboratories are well-equipped for parallel synthesis and automated purification. They house a wide range of analytical facilities including a 500MHz NMR spectrometer. 

We've areas for drug design activities, including the Roger Griffin Molecular Graphics Suite.

Researchers carrying out experiments in our Bedson Medicinal Chemistry lab.

Staff

Staff

Mike Waring
Celine Cano
Ian Hardcastle
Agnieszka Bronowska
Danny Cole

Greg Aldred
Christine Basmadjian
Suzannah Harnor
Stephen Hobson
Marie Lawson
Duncan Miller
Kate McAdam 
Jane Totobenaza 

Postgraduate students

Mohammed Alyasiri
Alfie Brennan
Daniel Brough
Gemma Davison
Conghao Gai
Amy Heptinstall
James Hunter
Shengying Lin
Daniel Lopez
Pasquale Morese
Alexia Papaioannou
Edwige Picazo
Shaun Stevens

 

Publications

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, epub ahead of print.

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.

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.

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.

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.

Harnor S, Brennan A, Cano C. Targeting DNA-Dependent Protein Kinase for Cancer Therapy. ChemMedChem 2017, epub ahead of print.

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, Epub ahead of print.

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.

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 2016, e-pub ahead of print.

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.

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 2016, (ePub ahead of Print).

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.

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 2016, epub ahead of print.