School of Natural and Environmental Sciences

Staff Profile

Professor Mike Waring

Professor of Medicinal Chemistry

Background

Scopus ID: 7102782045; ORCID ID: 0000-0002-9110-8783 

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Roles and Responsibilities

My research interests are concerned with the broad field of medicinal chemistry.  I lead the medicinal chemistry in the Drug Discovery Programme at the Northern Institute for Cancer Research – a Cancer Research UK Drug Discovery Centre.  I am a member of the Medicinal Chemistry and Chemical Biology Research Area.

I teach in the Medicinal Chemistry and Drug Design (Stage 2) and Metabolism and Toxicology (Stage 3) modules of the Chemistry with Medicinal Chemistry (BSc and MChem) and Drug Chemistry (MSc) degree programmes.

I am also the Director of Research for Chemistry.

Area of Expertise

Molecular and Materials Sciences

Awards and Esteem

2018 American Chemical Society Hero of Chemistry

for the discovery of the mutant EGFR inhibitor osimertinib (Tagrisso), a treatment for resistant forms of non-small cell lung cancer.

2017 Royal Society of Chemistry Malcolm Campbell Medal

for excellence in biological and medicinal chemistry.

2017 Elected Fellow of the Royal Society of Chemistry

2014 Royal Society of Chemistry Inaugural Biological and Medicinal Chemistry Sector Lectureship

in recognition of outstanding contributions to medicinal chemistry.

2010 Royal Society of Chemistry Capps Green Zomaya Memorial Medal

for outstanding contributions to medicinal chemistry and outstanding success in bringing medicines to the clinic.

2010 European Federation of Medicinal Chemistry Prize

for an outstanding young medicinal chemist in industry (runner up).

Qualifications

BSc(Hons), First Class, in Chemistry 1996 (University of Manchester)

PhD in Organic Chemistry 1999 (University of Manchester) with Prof. T. J. Donohoe

Previous Positions

April 2011 – August 2015: Principal Scientist in Medicinal Chemistry at AstraZeneca, Alderley Park, UK.

July 2001 – March 2011: Team Leader in Medicinal Chemistry at AstraZeneca, Alderley Park, UK

January 2000 - July 2001: Post-doctoral researcher in the group of Prof. P. D. Magnus, University of Texas at Austin, USA.

Research

Anti-cancer drug discovery

Within the Cancer Research UK Drug Discovery Programme, we run a portfolio of 6-8 projects focused on identifying new molecules for novel cancer targets in areas of unmet medical need.  These projects involve cutting-edge structure based drug design and employ modern methods for hit generation and optimisation.  The programme is run in collaboration with Astex Pharmaceuticals.

Development of chemical probes

We aim to develop small-molecule chemical probes for new protein targets for which no such probes exist and to work in collaboration to use these probes to elucidate new biology, with the aim of validating new therapeutic targets.

Tumour Targeting

The selective delivery of cytotoxic chemotherapy to tumour cells remains a key challenge in the treatment of cancer.  One of our interests is the development of new approaches to achieve this goal using small-molecules and antibodies as targeting agents.

New methods of hit generation

The identification of small-molecule ligands for protein targets remains a slow step in the medicinal chemistry and chemical biology fields.  We are interested in developing new methods for hit generation and optimisation, which could be applied generally to make this faster and increase success rates.

Funding

Our Research is funded by Cancer Research UKPancreatic Cancer Research Fund, EPSRC, Astex Pharmaceuticals, AstraZeneca and Newcastle University.  We are very grateful for their generous support.  Funded opportunities will be advertised when available.  Should you wish to seek independent funding to work in the group, we will work with you to support your applications.

Teaching

CHY2103 - Stage 2 Medicinal Chemistry - SAR and QSAR, enzyme inhibitors and G-protein coupled receptors.

CHY3109/3110/8822 - Stage 3 Medicinal Chemistry - Toxicology and Metabolism.

Publications

  • 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.
  • 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.
  • 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.
  • 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, Swarbirck 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.
  • 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.
  • Robb GR, McKerrecher D, Newcombe NJ, Waring MJ. A chemistry Wiki to facilitate and enhance chemical design in drug discovery. Drug Discovery Today 2013, 18(3-4), 141-147.
  • Plowright AT, Barton P, Bennett S, Birch AM, Birtles S, Buckett LK, Butlin RJ, Davies RDM, Ertan A, MorentinGutierrez P, Kemmitt PD, Leach AG, Svensson PH, Turnbull AV, Waring MJ. Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1. Med. Chem. Commun 2013, 4, 151.
  • Waring MJ, Bennett SNL, Campbell L, Davies RDM, Gerhardt S, Hargreaves D, Martin NG, Robb GR, Wilkinson G. Matched triplicate design sets in the optimisation of glucokinase activators – maximising medicinal chemistry information content. Med. Chem. Commun 2013, 4, 657.
  • Waring MJ, Birch AM, Birtles S, Buckett LK, Butlin RJ, Campbell L, MorentinGutierrez P, Kemmitt P, Leach AG, MacFaul P, ODonnell C, Turnbull AV. Optimisation of biphenylacetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353. Med. Chem. Commun 2013, 4, 159.
  • Waring MJ, Bennett SNL, Campbell L, Davies RDM, Hargreaves D, MacFaul P, Martin NG, Ogg D, Robb GR, Wilkinson G, Wood JM. Optimising pharmacokinetics of glucokinase activators with matched triplicate design sets – the discovery of AZD3651 and AZD9485. Med. Chem. Commun 2013, 4, 663.
  • McKerrecher D, Waring MJ. Property based design in the optimisation of glucokinase activators: from hit to clinic. Progr. Med. Chem 2013, 52, 1.
  • McKerrecher D, Waring MJ. Property-Based Design in the Optimisation of Benzamide Glucokinase Activators: From Hit to Clinic. Progr. Med. Chem 2013, 52, 1.
  • Ward RA, Anderton M, Ashton S, Box M, Butterworth S, Colclough N, Chorley CG, Chuaqui C, Cross D, Debreczeni JE, Eberlein C, Finlay MRV, Grist M, Hill GB, Klinowska TC, Lane C, Martin S, Orme JP, Smith P, Wang F, Waring MJ. Structure and reactivity based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). J. Med. Chem 2013, 56, 7025.
  • Waring MJ, Clarke DS, Fenwick MD, Godfrey L, Groombridge S, Johnstone C, McKerrecher D, Pike KG, Rayner J, Robb GR, Wilson I. Property based optimisation of glucokinase activators – the discovery of the Phase IIb candidate AZD1656. Med. Chem. Commun 2012, 3, 1077.
  • Moss T, Addie MS, Nowak T, Waring MJ. Room-temperature palladium-catalyzed coupling of heteroaryl amines with aryl or heteroaryl bromides. Synlett 2012, 23, 285.
  • Bonn P, Brink DM, Faegerhag J, Jurva U, Robb GR, Schnecke V, SvenssonHenriksson A, Waring MJ, Westerlund C. The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold. Bioorg. Med. Chem. Lett 2012, 22, 7302.
  • Waring MJ, Johnstone C, McKerrecher D, Pike KG, Robb GR. Matrix-based multiparameter optimisation of glucokinase activators: the discovery of AZD1092. Med. Chem. Commun 2011, 2, 775.
  • Waring MJ, Brogan IJ, Coghlan M, Johnstone C, Jones HB, Leighton B, McKerrecher D, Pike KG, Robb GR. Overcoming retinoic acid receptor-α based testicular toxicity in the optimisation of glucokinase activators. Med. Chem. Commun 2011, 2, 771.
  • Luker T, Alcaraz L, Chohan KK, Blomberg N, Brown DS, Butlin RJ, Elebring T, Griffin AM, Guile S, St-Gallay S, Swahn BM, Swallow S, Waring MJ, Wenlock MC, Leeson PD. Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules. Bioorg. Med. Chem. Lett 2011, 21, 5673.
  • Waring MJ. Lipophilicity in drug discovery. Expert Opinion on Drug Discovery 2010, 5(3), 235-248.
  • Tetlow DJ, Hennecke U, Raftery J, Waring MJ, Clarke DS, Clayden J. Sequential double α-arylation of N-allylureas by asymmetric deprotonation and N→C Aryl Migration. Organic Lett 2010, 12, 5442.
  • Waring MJ. Defining optimum lipophilicity and molecular weight ranges for drug candidates - molecular weight dependent lower logD limits based on permeability. Bioorg. Med. Chem. Lett 2009, 19, 2844.
  • Boyd S, Campbell L, Liao W, Meng Q, Peng Z, Wang W, Waring MJ. A one step synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines. Tetrahedron Lett 2008, 49, 7395.
  • Andrews DM, Stokes ESE, Carr GR, Matusiak ZS, Roberts CA, Waring MJ, Brady MC, Chresta CM, East SJ. Design and campaign synthesis of piperidine- and thiazole-based histone deacetylase inhibitors. Bioorg. Med. Chem. Lett 2008, 18, 2580.
  • Clark JS, Northall JM, Marlin F, Nay B, Wilson C, Blake AJ, Waring MJ. Synthetic studies on the cornexistins: synthesis of (±)-5-epi-hydroxycornexistin. Org. Biomol. Chem 2008, 6, 4012.
  • Waring MJ, Johnstone CJ. A quantitative assessment of hERG liability as a function of lipophilicity. Bioorg. Med. Chem. Lett 2007, 17, 1759.
  • Donohoe TJ, Mitchell L, Waring MJ, Helliwell M, Bell A, Newcombe NJ. Scope of the directed dihydroxylation: application to cyclic homoallylic alcohols and trihaloacetamides. Org. Biomol. Chem 2003, 1, 2173.
  • Donohoe TJ, Blades K, Moore PR, Waring MJ, Winter JJG, Helliwell M, Newcombe NJ, Stemp G. Directed dihydroxylation of cyclic allylic alcohols and trichloroacetamides using OsO4/TMEDA. J. Org. Chem 2002, 67, 7946.
  • Donohoe TJ, Mitchell L, Waring MJ, Helliwell M, Bell A, Newcombe NJ. Homoallylic alcohols and trichloroacetamides as hydrogen bond donors for directed dihydroxylation. Tetrahedron Lett 2001, 42, 8951.
  • Magnus P, Waring MJ, Ollivier C, Lynch V. Stereoselective synthesis of the bicyclo[5.3.0]decane portion of the diterpene antibiotic guanacastepene using a pyrylium-ylide [5+2] cycloaddition reaction. Tetrahedron Lett 2001, 42, 4947.
  • Magnus P, Waring MJ, Scott DA. Conjugate reduction of α,β-unsaturated ketones using an MnIII catalyst, phenylsilane and isopropyl alcohol. Tetrahedron Lett 2000, 41, 9731.
  • Magnus P, Payne AH, Waring MJ, Scott DA, Lynch V. Conversion of α,β-unsaturated ketones into α-hydroxy ketones using an MnIII catalyst, phenylsilane and dioxygen: acceleration of conjugate hydride reduction by dioxygen. Tetrahedron Lett 2000, 41, 9725.
  • Donohoe TJ, Waring MJ, Newcombe NJ. Enhanced stereoselectivity in the catalytic dihydroxylation of acyclic allylic alcohols. SynLett 2000, 149.
  • Donohoe TJ, Waring MJ, Newcombe NJ. syn Stereocontrol in the directed dihydroxylation of acyclic allylic alcohols. Tetrahedron Lett 1999, 40, 6881.
  • Donohoe TJ, Harji RR, Moore PR, Waring MJ. Applications of stoichiometric organotransition metal complexes in organic synthesis. J. Chem. Soc., Perkin Trans. 1 1998, 819.
  • Donohoe TJ, Blades K, Helliwell M, Waring MJ, Newcombe NJ. The synthesis of (+)-Pericosine B. Tetrahedron Lett 1998, 39, 8755.
  • Donohoe TJ, Moore PR, Waring MJ, Newcombe NJ. The directed dihydroxylation of allylic alcohols. Tetrahedron Lett 1997, 38, 5027.