Background

History

Dr Ian Hardcastle received his first degree from Bristol University in 1987. He received his PhD in organic synthesis in 1990, from Manchester University, with Dr Peter Quayle. This was followed by a post-doctoral fellowship in the CRC Centre for Cancer Therapeutics at The Institute of Cancer Research with Professor Mike Jarman. Work at the ICR included: studies of the structure activity relationships for tamoxifen analogues, studies into the genotoxic mechanism of tamoxifen. The development of the novel CYP17a inhibitor abiraterone (Zytiga) licenced for the treatment of castrate resistant prostate cancer. The synthesis of novel inhibitors of the Farnesyl Transferase enzyme and the development of novel template-based combinatorial libraries for lead discovery.

In November 1999 he joined the Drug Discovery Programme in the Cancer Research Unit now the Newcastle Cancer Centre at the Northern Institute for Cancer Research (NICR), Newcastle University, as a Lecturer in Medicinal Chemistry and is now Reader in Medicinal Chemistry.

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SCOPUS

 

Research

Principal Research Interests: medicinal chemistry and drug discovery, targeted anti-cancer agents.

 

The medicinal chemistry team (C Cano, BT Golding, IR Hardcastle, and M Waring) is part of the Drug Discovery Group within the NICR. Working closely with basic cancer biologists, structural biologists, pharmacologists, imaging specialists, and clinical scientists, the overall aim of the programme is to discover novel small-molecule inhibitors of cancer targets which can be developed into new treatments for cancer patients.

Targets are selected based on an understanding of the underlying cancer biology and their clinical relevance. Current projects include the discovery of small-molecule MDM2-p53 protein protein interactions, the discovery of small-molecule ERK5 inhibitors, and hit-discovery studies for other novel cancer targets.

Contemporary, medicinal chemistry methods are used in all projects. including high throughput screening to identify hit compounds (through external collaborations), and structural biology to enable rational drug-design. High-throughput synthesis, utilising solution-and solid-phase multiple-parallel approaches and microwave heating, is used to determine structure-activity relationships and rapidly optimise biological activities and pharmaceutical properties for lead compounds.

Computational chemistry and informatics are essential tools, and the group uses the Dotmatics database suite, and Optibrium's StarDrop for predicting properties.

Teaching

School of Natural and Environmental Sciences

BSc/MChem Chemistry and Chemistry with Medicinal Chemistry

CHY1101 - Organic Chemistry
CHY1102 - Fundamentals of Biological and Medicinal Chemistry
CHY2101 - Organic Chemistry
CHY2103 - Medicinal Chemistry
CHY3108 - Organic Chemistry
CHY3011 - Literature Project
CHY8421/8821 - Advanced Methods in Drug Discovery
CHY8411/8412 - Research Project

MSc Drug Chemistry

CHY8821 - Modern Methods in Drug Discovery
CHY8812 - Research Preparation

CHY8827 - Biological and Medicinal Chemistry

Medical School

MRes Translational Medicine and Therapeutics - L12 The role of medicinal chemistry

Publications

• Wood D, Lopez-Fernandez JD, Knight LE, Al-Khawaldeh I, Gai C, Lin S, Martin MP, Miller DC, Cano C, Endicott JA, Hardcastle IR, Noble MEM, Waring MJ. FragLites - minimal, halogenated fragments displaying pharmacophore doublets. An efficient approach to druggability assessment and hit generation. Journal of Medicinal Chemistry 2019, 62(7), 3741-3752.
• 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(11), 1369–1388.
• 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.
• Chessari G, Howard S, Buck IM, Cons BD, Johnson CN, Holvey RS, Rees DC, St Denis JD, Tamanini E, Golding BT, Hardcastle IR, Cano CF, Miller DC, Noble MEM, Griffin RJ, Osborne JD, Peach J, Lewis A, Hirst KL, Whittaker BP, Watson DR. ISOINDOLINONE INHIBITORS OF THE MDM2-P53 INTERACTION HAVING ANTICANCER ACTIVITY. PCT/GB2016/053041, 06/04/2017.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 Chemistry 2015, 7(5), 631-645.
• 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.
• 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.
• 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.
• 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.
• Cinatl J, Speidel D, Hardcastle I, Michelis M. Resistance acquisition to MDM2 inhibitors. Biochemical Society Transactions 2014, 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 S_NAr Reactions of Heterocycles with Arylamines. Chemistry: A European Journal 2014, 20(8), 2311-2317.
• Cano C, Saravanan K, Bailey C, Bardos J, Curtin NJ, Frigerio M, Golding BT, Hardcastle IR, Hummersone MG, Menear KA, Newell DR, Richardson CJ, Shea K, Smith GCM, Thommes P, Ting A, Griffin RJ. 1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK PI3-K Inhibitory Activity. Journal of Medicinal Chemistry 2013, 56(16), 6386-6401.
• Blackburn TJ, Ahmed S, Coxon CR, Liu JF, Lu XH, Golding BT, Griffin RJ, Hutton C, Newell DR, Ojo S, Watson AF, Zaytzev A, Zhao Y, Lunec J, Hardcastle IR. Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions. MedChemComm 2013, 4(9), 1297-1304.
• Lebraud H, Cano C, Carbain B, Hardcastle IR, Harrington RW, Griffin RJ, Golding BT. Trifluoroethanol solvent facilitates selective N-7 methylation of purines. Organic & Biomolecular Chemistry 2013, 11(11), 1874-1878.
• Coffey K, Blackburn TJ, Cook S, Golding BT, Griffin RJ, Hardcastle IR, Hewitt L, Huberman K, McNeill HV, Newell DR, Roche C, Ryan-Munden CA, Watson A, Robson CN. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS One 2012, 7(10), e45539.
• Clapham KM, Rennison T, Jones G, Craven F, Bardos J, Golding BT, Griffin RJ, Haggerty K, Hardcastle IR, Thommes P, Ting A, Cano C. Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives. Organic & Biomolecular Chemistry 2012, 10(33), 6747-6757.
• Clapham KM, Bardos J, Finlay R, Golding BT, Griffen EJ, Griffin RJ, Hardcastle IR, Menear KA, Ting A, Turner P, Young GL, Cano C. DNA-dependent protein kinase (DNA-PK) inhibitors: Structure–activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain. Bioorganic & Medicinal Chemistry Letters 2011, 21(3), 966-970.
• Hardcastle IR, Liu J, Valeur E, Watson A, Ahmed SU, Blackburn TJ, Bennaceur K, Clegg W, Drummond C, Endicott JA, Golding BT, Griffin RJ, Gruber J, Haggerty K, Harrington RW, Hutton C, Kemp S, Lu X, McDonnell JM, Newell DR, Noble ME, Payne SL, Revill CH, Riedinger C, Xu Q, Lunec J. Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency. Journal of Medicinal Chemistry 2011, 54(5), 1233-1243.
• Watson AF, Liu JF, Bennaceur K, Drummond CJ, Endicott JA, Golding BT, Griffin RJ, Haggerty K, Lu XH, McDonnell JM, Newell DR, Noble MEM, Revill CH, Riedinger C, Xu Q, Zhao Y, Lunec J, Hardcastle IR. MDM2-p53 protein-protein interaction inhibitors: A-ring substituted isoindolinones. Bioorganic & Medicinal Chemistry Letters 2011, 21(19), 5916-5919.
• Thomas HD, Wang LZ, Roche C, Bentley J, Cheng YZ, Hardcastle IR, Golding BT, Griffin RJ, Curtin NJ, Newell DR. Preclinical in vitro and in vivo evaluation of the potent and specific cyclin-dependent kinase 2 inhibitor NU6102 and a water soluble prodrug NU6301. European Journal of Cancer 2011, 47(13), 2052-2059.
• Riedinger C, Noble ME, Wright DJ, Mulks F, Hardcastle I, Endicott JA, McDonnell JM. Understanding small-molecule binding to MDM2: Insights into structural effects of isoindolinone inhibitors from NMR spectroscopy. Chemical Biology and Drug Design 2011, 77(5), 301-308.
• Rodriguez SA, Clapham KM, Barrett L, Cano C, Desage ME, Griffin RJ, Hardcastle IR, Payne SL, Rennison T, Richardson C, Golding BT. Versatile Synthesis of Functionalised Dibenzothiophenes via Suzuki Coupling and Microwave-assisted Ring Closure. Organic & Biomolecular Chemistry 2011, 9(17), 6066-6074.
• Cano C, Golding BT, Haggerty K, Hardcastle IR, Peacock M, Griffin RJ. Atropisomeric 8-arylchromen-4-ones exhibit enantioselective inhibition of the DNA-dependent protein kinase (DNA-PK). Organic & Biomolecular Chemistry 2010, 8(8), 1922-1928.
• Cano C, Barbeau OR, Bailey C, Cockcroft XL, Curtin NJ, Duggan H, Frigerio M, Golding BT, Hardcastle IR, Hummersone MG, Knights C, Menear KA, Newell DR, Richardson CJ, Smith GC, Spittle B, Griffin RJ. DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype. Journal of Medicinal Chemistry 2010, 53(24), 8498-8507.
• Payne SL, Rodriguez-Aristegui S, Bardos J, Cano C, Golding BT, Hardcastle IR, Peacock M, Parveen N, Griffin RJ. Mapping the ATP-binding domain of DNA-dependent protein kinase (DNA-PK) with coumarin- and isocoumarin-derived inhibitors. Bioorganic & Medicinal Chemistry Letters 2010, 20(12), 3649-3653.
• Marchetti F, Cano C, Curtin NJ, Golding BT, Griffin RJ, Haggerty K, Newell DR, Parsons RJ, Payne SL, Wang LZ, Hardcastle IR. Synthesis and biological evaluation of 5-substituted O⁴-alkylpyrimidines as CDK2 inhibitors. Organic & Biomolecular Chemistry 2010, 8(10), 2397-2407.
• Wong C, Griffin RJ, Hardcastle IR, Northen JS, Wang LZ, Golding BT. Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated S_N2 reactivity of 2,2,2-trifluoroethoxysulfonates. Organic & Biomolecular Chemistry 2010, 8(10), 2457-2464.
• Murr M, Cano C, Golding BT, Hardcastle IR, Hummersome M, Frigerio M, Curtin NJ, Menear K, Richardson C, Smith G, Griffin R. 8-Biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK). Bioorganic and Medicinal Chemistry Letters 2008, 18(17), 4885-4890.
• Riedinger C, Endicott JA, Kemp SJ, Smyth LA, Watson A, Valeur E, Golding BT, Griffin RJ, Hardcastle IR, Noble ME, McDonnell JM. Analysis of Chemical Shift Changes Reveals the Binding Modes of Isoindolinone Inhibitors of the MDM2-p53 Interaction. Journal of the American Chemical Society 2008, 130(47), 16038-16044.
• Hardcastle IR. Inhibitors of the MDM2-p53 interaction as anticancer drugs. Drugs of the Future 2007, 32(10), 883-896.
• Hollick J, Rigoreau L, Cano-Soumillac C, Cockcroft X, Curtin NJ, Frigerio M, Golding BT, Guiard S, Hardcastle IR, Hickson I, Hummersone M, Menear K, Martin N, Matthews I, Newell DR, Ord R, Richardson C, Smith G, Griffin RJ. Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase. Journal of Medicinal Chemistry 2007, 50(8), 1958-1972.
• Barbeau OR, Cano-Soumillac C, Griffin RJ, Hardcastle IR, Smith GCM, Richardson C, Clegg W, Harrington RW, Golding BT. Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase. Organic & Biomolecular Chemistry 2007, 5(16), 2670-2677.
• Hardcastle, I.R., Ahmed, S., Atkins, H., Farnie, G., Golding, B.T., Griffin, R.J., Guyenne, S., Hutton,C., Källblad, P., Kemp, S., Kitching, M.S., Newell, D.R., Norbedo, S., Northen, J.S., Reid, R.J., Saravanan, K., Willems, H., Lunec, J. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. Journal of Medicinal Chemistry 2006, 49(21), 6209-6221.
• Hardcastle I, Ahmed S, Atkins H, Calvert AH, Curtin NJ, Farnie G, Golding BT, Griffin R, Guyenne S, Hutton C, Källblad P, Kemp S, Kitching M, Newell D, Norbedo S, Northen J, Reid R, Saravanan K, Willems H, Lunec J. Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction. Bioorganic and Medicinal Chemistry Letters 2005, 15(5), 1515-1520.