Research Topics
Species | Ian R HardcastleSummaryAffiliation: University of Newcastle Country: UK Publications
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Publications
Designing inhibitors of cyclin-dependent kinasesIan 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...
Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potencyIan 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...- Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffoldIan 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... - N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2Ian 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... - Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approachIan 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... - Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interactionIan 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... - 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 vitroRoger 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... - Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2Kerry 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.... - 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 teJonathan 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... - Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2Francesco 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... - Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone librariesJustin 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... - 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... - 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2Veronique 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... - Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivativesKate 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... - Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitorsFrancesco 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)... - Mapping the ATP-binding domain of DNA-dependent protein kinase (DNA-PK) with coumarin- and isocoumarin-derived inhibitorsSara 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... - Searching for cyclin-dependent kinase inhibitors using a new variant of the cope eliminationRoger 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... - MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinonesAnna 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... - 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 chemotypeCeline 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.... - 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.... - Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinaseOlivier 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)... - Preclinical in vitro and in vivo evaluation of the potent and specific cyclin-dependent kinase 2 inhibitor NU6102 and a water soluble prodrug NU6301Huw 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... - Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closureSonsoles 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... - DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domainKate 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.... - Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonatesChristopher 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... - 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... - 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 inhibitorsSonsoles 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... 
Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancerKelly 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...- A new strategy for the synthesis of taurine derivatives using the 'safety-catch' principle for the protection of sulfonic acidsSonja 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... - Structure-based design of a potent purine-based cyclin-dependent kinase inhibitorThomas 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... - Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulationMarzia 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... - An evaluation of the ability of pifithrin-alpha and -beta to inhibit p53 function in two wild-type p53 human tumor cell linesMike 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...