Ian R Hardcastle

Summary

Affiliation: University of Newcastle
Country: UK

Publications

  1. ncbi request reprint Designing inhibitors of cyclin-dependent kinases
    Ian R Hardcastle
    Northern Institute for Cancer Research University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 4RU, United Kingdom
    Annu Rev Pharmacol Toxicol 42:325-48. 2002
  2. ncbi request reprint Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold
    Ian R Hardcastle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle, NE1 7RU, United Kingdom
    J Med Chem 49:6209-21. 2006
  3. doi request reprint Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency
    Ian R Hardcastle
    Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle NE1 7RU, United Kingdom
    J Med Chem 54:1233-43. 2011
  4. ncbi request reprint Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction
    Ian R Hardcastle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK
    Bioorg Med Chem Lett 15:1515-20. 2005
  5. ncbi request reprint Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach
    Ian R Hardcastle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle upon Tyne NE1 7RU, UK
    J Med Chem 48:7829-46. 2005
  6. ncbi request reprint N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2
    Ian R Hardcastle
    Northern Institute for Cancer Research, Bedson Building, School of Natural Sciences, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
    J Med Chem 47:3710-22. 2004
  7. ncbi request reprint Selective benzopyranone and pyrimido[2,1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro
    Roger J Griffin
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, The University, Newcastle upon Tyne NE1 7RU, UK
    J Med Chem 48:569-85. 2005
  8. ncbi request reprint Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2
    Kerry L Sayle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
    Bioorg Med Chem Lett 13:3079-82. 2003
  9. ncbi request reprint 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 te
    Jonathan J Hollick
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
    J Med Chem 50:1958-72. 2007
  10. ncbi request reprint Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2
    Francesco Marchetti
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, UKNE1 7RU
    Org Biomol Chem 5:1577-85. 2007

Collaborators

Detail Information

Publications36

  1. ncbi request reprint Designing inhibitors of cyclin-dependent kinases
    Ian R Hardcastle
    Northern Institute for Cancer Research University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 4RU, United Kingdom
    Annu Rev Pharmacol Toxicol 42:325-48. 2002
    ..The crystal structures of a number of key inhibitors bound to cdk2 can be used to explain the observed structure-activity relationships within the compound series and to guide the design of more potent inhibitors...
  2. ncbi request reprint Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold
    Ian R Hardcastle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle, NE1 7RU, United Kingdom
    J Med Chem 49:6209-21. 2006
    ..3 +/- 0.9 microM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line...
  3. doi request reprint Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency
    Ian R Hardcastle
    Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle NE1 7RU, United Kingdom
    J Med Chem 54:1233-43. 2011
    ..Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays...
  4. ncbi request reprint Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction
    Ian R Hardcastle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK
    Bioorg Med Chem Lett 15:1515-20. 2005
    ..3 +/- 0.9 microM in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line...
  5. ncbi request reprint Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach
    Ian R Hardcastle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle upon Tyne NE1 7RU, UK
    J Med Chem 48:7829-46. 2005
    ..5 at 10% survival being observed at 0.5 microM. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated...
  6. ncbi request reprint N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2
    Ian R Hardcastle
    Northern Institute for Cancer Research, Bedson Building, School of Natural Sciences, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
    J Med Chem 47:3710-22. 2004
    ..X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity...
  7. ncbi request reprint Selective benzopyranone and pyrimido[2,1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro
    Roger J Griffin
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, The University, Newcastle upon Tyne NE1 7RU, UK
    J Med Chem 48:569-85. 2005
    ..3 at 10% survival being observed with an inhibitor concentration of 5 microM. This study identified these structural classes as novel DNA-PK inhibitors and delineated initial structure-activity relationships against DNA-PK...
  8. ncbi request reprint Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2
    Kerry L Sayle
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
    Bioorg Med Chem Lett 13:3079-82. 2003
    ....
  9. ncbi request reprint 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 te
    Jonathan J Hollick
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
    J Med Chem 50:1958-72. 2007
    ..One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50=220 nM) effectively sensitized HeLa cells to the topoisomerase II inhibitor etoposide in vitro...
  10. ncbi request reprint Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2
    Francesco Marchetti
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, UKNE1 7RU
    Org Biomol Chem 5:1577-85. 2007
    ..The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A...
  11. ncbi request reprint 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2
    Veronique Mesguiche
    Northern Institute of Cancer Research and Department of Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
    Bioorg Med Chem Lett 13:217-22. 2003
    ..Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series...
  12. ncbi request reprint Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries
    Justin J J Leahy
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
    Bioorg Med Chem Lett 14:6083-7. 2004
    ..These studies resulted in the identification of 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) as a highly potent and selective DNA-PK inhibitor (IC50=14 nM), exhibiting ATP-competitive inhibition kinetics...
  13. doi request reprint Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors
    Francesco Marchetti
    Northern Institute for Cancer Research, Bedson Building, Newcastle University, Newcastle upon Tyne, UK NE1 7RU
    Org Biomol Chem 8:2397-407. 2010
    ..4 nM). The 5-formyl derivatives show selectivity for CDK2 over other CDK family members, and are growth inhibitory in tumour cells (e.g. 22j, GI(50) = 0.57 microM)...
  14. ncbi request reprint 2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK)
    Jonathan J Hollick
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
    Bioorg Med Chem Lett 13:3083-6. 2003
    ..2-0.4 microM range...
  15. doi request reprint Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives
    Kate M Clapham
    Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK
    Org Biomol Chem 10:6747-57. 2012
    ..Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer...
  16. ncbi request reprint Mapping the ATP-binding domain of DNA-dependent protein kinase (DNA-PK) with coumarin- and isocoumarin-derived inhibitors
    Sara L Payne
    Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK
    Bioorg Med Chem Lett 20:3649-53. 2010
    ..Structure-activity relationships for DNA-PK inhibition were broadly consistent, albeit with a reduction of potency compared with the parent chromenone...
  17. doi request reprint 1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity
    Celine Cano
    Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom
    J Med Chem 56:6386-401. 2013
    ..Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors...
  18. pmc Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer
    Kelly Coffey
    Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
    PLoS ONE 7:e45539. 2012
    ..Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer...
  19. doi request reprint MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones
    Anna F Watson
    Newcastle Cancer Centre at the Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle, NE1 7RU, UK
    Bioorg Med Chem Lett 21:5916-9. 2011
    ..Compounds 10a and (-)-10a increase p53 protein levels, activate p53-dependent MDM2 and p21 transcription in MDM2 amplified cells, and show improved selectivity for growth inhibition in wild type p53 cell lines over the parent compound...
  20. doi request reprint 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
    Celine Cano
    Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, UK
    J Med Chem 53:8498-507. 2010
    ....
  21. ncbi request reprint 8-Biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK)
    Marine Desage-El Murr
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
    Bioorg Med Chem Lett 18:4885-90. 2008
    ....
  22. ncbi request reprint Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase
    Olivier R Barbeau
    Northern Institute for Cancer Research, Bedson Building, Newcastle University, Newcastle upon Tyne, UK NE1 7RU
    Org Biomol Chem 5:2670-7. 2007
    ..R. Hardcastle, X. Cockcroft, N. J. Curtin, M. Desage El-Murr, J. J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. M. Smith and R. J. Griffin, J. Med. Chem., 2005, 48, 7829-7846)...
  23. doi request reprint Preclinical in vitro and in vivo evaluation of the potent and specific cyclin-dependent kinase 2 inhibitor NU6102 and a water soluble prodrug NU6301
    Huw D Thomas
    Newcastle Cancer Centre at the Northern Institute for Cancer Research, Paul O Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
    Eur J Cancer 47:2052-9. 2011
    ..007, respectively) following NU6301 administration. NU6102 and its prodrug NU6301 have pharmacological properties consistent with CDK2 inhibition, and represent useful tool molecules for the evaluation of CDK2 as a target in cancer...
  24. ncbi request reprint Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure
    Sonsoles Rodriguez-Aristegui
    Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, United Kingdom NE1 7RU
    Org Biomol Chem 9:6066-74. 2011
    ..The data indicate permissive elaboration of hydroxyl at C-8 or C-9, enabling the possibility of improved pharmaceutical properties, whilst retaining potency against DNA-PK...
  25. ncbi request reprint Searching for cyclin-dependent kinase inhibitors using a new variant of the cope elimination
    Roger J Griffin
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne, UK
    J Am Chem Soc 128:6012-3. 2006
    ..The synthetic methodology developed can be utilized in multiple-parallel format and has numerous potential applications in medicinal chemistry...
  26. doi request reprint Trifluoroethanol solvent facilitates selective N-7 methylation of purines
    Honorine Lebraud
    Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom
    Org Biomol Chem 11:1874-8. 2013
    ..Subjecting the resulting cationic species to microwave irradiation releases an N(7)-methyl- or ethyl-purine. This one-pot procedure is an efficient regiospecific method applicable to diverse substrates...
  27. doi request reprint Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates
    Christopher Wong
    Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, UK NE1 7RU
    Org Biomol Chem 8:2457-64. 2010
    ..5-1.5 microM range. N-(4-tert-Butylphenyl)-1-[3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methanesulfonamide was markedly less active (IC(50) = 34 microM), suggesting a steric effect within the ATP-binding domain...
  28. doi request reprint DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain
    Kate M Clapham
    Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, United Kingdom
    Bioorg Med Chem Lett 21:966-70. 2011
    ....
  29. doi request reprint Trifluoroacetic acid in 2,2,2-trifluoroethanol facilitates S(N)Ar reactions of heterocycles with arylamines
    Benoit Carbain
    Newcastle Cancer Centre, Northern Institute for Cancer Research, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU UK
    Chemistry 20:2311-7. 2014
    ..Reactions can be performed with either conventional heating or microwave irradiation, with the latter often giving improved yields. ..
  30. ncbi request reprint Judicious application of allyl protecting groups for the synthesis of 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl triflate, a key precursor of DNA-dependent protein kinase inhibitors
    Sonsoles Rodriguez Aristegui
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
    Org Lett 8:5927-9. 2006
    ..Both syntheses depend on the judicious use of allyl protecting groups...
  31. doi request reprint Atropisomeric 8-arylchromen-4-ones exhibit enantioselective inhibition of the DNA-dependent protein kinase (DNA-PK)
    Celine Cano
    Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, United KingdomNE1 7RU
    Org Biomol Chem 8:1922-8. 2010
    ..Biological evaluation against DNA-PK of the pairs of atropisomers showed a marked difference in potency, with only one enantiomer being biologically active...
  32. doi request reprint Model system for irreversible inhibition of Nek2: thiol addition to ethynylpurines and related substituted heterocycles
    Honorine Lebraud
    Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
    Org Biomol Chem 12:141-8. 2014
    ..The results of this study indicate heterocyclic scaffolds that are likely to be more promising for inhibition of Nek2 and other kinases containing a reactive cysteine. ..
  33. ncbi request reprint A new strategy for the synthesis of taurine derivatives using the 'safety-catch' principle for the protection of sulfonic acids
    Sonja Seeberger
    Northern Institute for Cancer Research, School of Natural Sciences Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
    Org Biomol Chem 5:132-8. 2007
    ..The method developed should be generally applicable to the protection of sulfonic acids and is amenable to a multiparallel format...
  34. ncbi request reprint Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation
    Marzia Pennati
    Department of Experimental Oncology, Istituto Nazionale dei Tumori, Milan, Italy
    Mol Cancer Ther 4:1328-37. 2005
    ..Results from this study indicate that NU6140 significantly potentiates the apoptotic effect of paclitaxel, with inhibition of survivin expression/phosphorylation as the potential mechanism...
  35. ncbi request reprint Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor
    Thomas G Davies
    Laboratory of Molecular Biophysics and Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK
    Nat Struct Biol 9:745-9. 2002
    ..Furthermore, the potency of O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions...
  36. ncbi request reprint An evaluation of the ability of pifithrin-alpha and -beta to inhibit p53 function in two wild-type p53 human tumor cell lines
    Mike I Walton
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton Surrey
    Mol Cancer Ther 4:1369-77. 2005
    ..In conclusion, neither PFT-alpha nor -beta can be regarded as a ubiquitous inhibitor of p53 function, and caution should be exercised in the use of these agents as specific p53 inhibitors...