Hardcastle, Ian - Newcastle University

个人简介

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.

研究领域

medicinal chemistry and drug discovery, targeted anti-cancer agents

近期论文

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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. 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). 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. 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. 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 SNAr 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.