P Workman

Summary

Affiliation: Institute of Cancer Research
Country: UK

Publications

  1. ncbi request reprint New drug targets for genomic cancer therapy: successes, limitations, opportunities and future challenges
    P Workman
    CRC Centre for Cancer Therapeutics, Institute for Cancer Research, Sutton, Surrey, SN2 5NG, UK
    Curr Cancer Drug Targets 1:33-47. 2001
  2. pmc Finding the needle in the haystack: why high-throughput screening is good for your health
    G Wynne Aherne
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Breast Cancer Res 4:148-54. 2002
  3. ncbi request reprint Pharmacogenomics in cancer drug discovery and development: inhibitors of the Hsp90 molecular chaperone
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Block E, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Cancer Detect Prev 26:405-10. 2002
  4. ncbi request reprint Challenges of PK/PD measurements in modern drug development
    P Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SN2 5NG, UK
    Eur J Cancer 38:2189-93. 2002
  5. ncbi request reprint Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: unfolding the relationship between pharmacokinetics and pharmacodynamics
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SN2 5NG, United Kingdom
    Mol Cancer Ther 2:131-8. 2003
  6. ncbi request reprint Translating basic cancer research into new cancer therapeutics
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, SM2 5NG, UK
    Trends Mol Med 8:S1-9. 2002
  7. ncbi request reprint Scoring a bull's-eye against cancer genome targets
    P Workman
    CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK
    Curr Opin Pharmacol 1:342-52. 2001
  8. ncbi request reprint Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis
    I Hostein
    Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
    Cancer Res 61:4003-9. 2001
  9. pmc Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors
    J R Smith
    Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Surrey, UK
    Oncogene 28:157-69. 2009
  10. pmc A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days
    C Benson
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK
    Br J Cancer 96:29-37. 2007

Detail Information

Publications91

  1. ncbi request reprint New drug targets for genomic cancer therapy: successes, limitations, opportunities and future challenges
    P Workman
    CRC Centre for Cancer Therapeutics, Institute for Cancer Research, Sutton, Surrey, SN2 5NG, UK
    Curr Cancer Drug Targets 1:33-47. 2001
    ..However, many challenges remain as we test the vision of individualised combinatorial genome-based therapy, using drugs targeted to every significant molecular abnormality in cancer...
  2. pmc Finding the needle in the haystack: why high-throughput screening is good for your health
    G Wynne Aherne
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Breast Cancer Res 4:148-54. 2002
    ..Examples of successful drug discovery programmes based on high-throughput screening are described, and these offer potential in the treatment of breast cancer and other malignancies...
  3. ncbi request reprint Pharmacogenomics in cancer drug discovery and development: inhibitors of the Hsp90 molecular chaperone
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Block E, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Cancer Detect Prev 26:405-10. 2002
    ..The use of the postgenomic technology of gene expression microarrays in cancer pharmacology and drug development will be exemplified...
  4. ncbi request reprint Challenges of PK/PD measurements in modern drug development
    P Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SN2 5NG, UK
    Eur J Cancer 38:2189-93. 2002
  5. ncbi request reprint Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: unfolding the relationship between pharmacokinetics and pharmacodynamics
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SN2 5NG, United Kingdom
    Mol Cancer Ther 2:131-8. 2003
  6. ncbi request reprint Translating basic cancer research into new cancer therapeutics
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, SM2 5NG, UK
    Trends Mol Med 8:S1-9. 2002
  7. ncbi request reprint Scoring a bull's-eye against cancer genome targets
    P Workman
    CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK
    Curr Opin Pharmacol 1:342-52. 2001
    ..Drugs acting on a range of new genome-based molecular targets are now in preclinical and clinical development...
  8. ncbi request reprint Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis
    I Hostein
    Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
    Cancer Res 61:4003-9. 2001
    ....
  9. pmc Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors
    J R Smith
    Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Surrey, UK
    Oncogene 28:157-69. 2009
    ..These results support an essential role for CDC37 in concert with HSP90 in maintaining oncogenic protein kinase clients and endorse the therapeutic potential of targeting CDC37 in cancer...
  10. pmc A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days
    C Benson
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK
    Br J Cancer 96:29-37. 2007
    ..No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer...
  11. ncbi request reprint Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer
    L R Kelland
    CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey SM2 5NG, United Kingdom
    Clin Cancer Res 7:3544-50. 2001
    ....
  12. ncbi request reprint Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol
    V Smith
    CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
    Mol Pharmacol 60:885-93. 2001
    ..However, transfection of cyclin E to increase expression of this protein did not result in an increase in resistance to flavopiridol. Thus, up-regulation of cyclin E alone does not seem to cause resistance to this cdk inhibitor...
  13. ncbi request reprint Establishment of an isogenic human colon tumor model for NQO1 gene expression: application to investigate the role of DT-diaphorase in bioreductive drug activation in vitro and in vivo
    S Y Sharp
    CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
    Mol Pharmacol 58:1146-55. 2000
    ..This isogenic model should be valuable for mechanistic studies and bioreductive drug development...
  14. ncbi request reprint Drugging the cancer kinome: progress and challenges in developing personalized molecular cancer therapeutics
    P Workman
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey
    Cold Spring Harb Symp Quant Biol 70:499-515. 2005
    ..Three projects in which the author's laboratory is involved are reviewed in detail. These involve the discovery and development of inhibitors of cyclin-dependent kinases, phosphoinositide 3-kinases, and the Hsp90 molecular chaperone...
  15. pmc Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026
    B P Nutley
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton SM2 5NG, UK
    Br J Cancer 93:1011-8. 2005
    ..The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg(-1) i.p. in order to obtain the drug exposure required for radiosensitisation...
  16. ncbi request reprint The role of functional and molecular imaging in cancer drug discovery and development
    B M Seddon
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Br J Radiol 76:S128-38. 2003
    ....
  17. ncbi request reprint Drug discovery strategies: technologies to accelerate translation from target to drug
    P Workman
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
    J Chemother 16:13-5. 2004
    ..Similarly, the drug discovery process is being accelerated by a range of other valuable technologies. Using these approaches, we can expect to see a range of personalised molecular therapeutics becoming available for cancer treatment...
  18. ncbi request reprint The impact of genomic and proteomic technologies on the development of new cancer drugs
    P Workman
    Cancer Research UK, Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, UK
    Ann Oncol 13:115-24. 2002
  19. ncbi request reprint Inhibition of Kirsten-ras expression in human colorectal cancer using rationally selected Kirsten-ras antisense oligonucleotides
    P J Ross
    Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom
    Mol Cancer Ther 1:29-41. 2001
    ....
  20. ncbi request reprint Gene expression microarray analysis in cancer biology, pharmacology, and drug development: progress and potential
    P A Clarke
    Cancer Research Campaign Centre for Cancer Therapeutics, E Block, Institute of Cancer Research, 15 Cotswold Road, SM2 5NG, Sutton, Surrey, UK
    Biochem Pharmacol 62:1311-36. 2001
    ..As a result of further technological improvements and decreasing costs, the use of microarrays will become an essential and potentially routine tool for cancer and biomedical research...
  21. ncbi request reprint A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D
    S Rayter
    Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
    Oncogene 27:1036-44. 2008
    ..These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor...
  22. pmc Clinical anticancer drug development: targeting the cyclin-dependent kinases
    C Benson
    Section of Medicine and Cancer Research UK Centre for Cancer Therapeutics, Institute for Cancer Research and Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
    Br J Cancer 92:7-12. 2005
    ..The critical nature of these proteins in cell cycling raises hope that targeting them may result in selective cytotoxicity and valuable anticancer activity...
  23. pmc A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy
    C P Lee
    Cancer Research UK Centre for Cancer Therapeutics, Cancer Research UK Clinical Magnetic Resonance Research Group and Section of Medicine, The Institute of Cancer Research and Drug Development Unit, The Royal Marsden Hospital, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Br J Cancer 101:1860-8. 2009
    ..Preliminary MRS studies demonstrated some evidence of 19F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19F MRS signal...
  24. pmc Guidelines for the welfare and use of animals in cancer research
    P Workman
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Br J Cancer 102:1555-77. 2010
    ....
  25. pmc Characterisation of molecular events following cisplatin treatment of two curable ovarian cancer models: contrasting role for p53 induction and apoptosis in vivo
    P A Clarke
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, UK
    Br J Cancer 91:1614-23. 2004
    ..Our observations show that a marked in vivo response to cisplatin can occur via p53-dependent apoptosis or independently of p53 status in human ovarian xenografts...
  26. pmc Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI
    M Beloueche-Babari
    Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK
    Br J Cancer 109:1562-9. 2013
    ....
  27. pmc Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns
    A S Moore
    Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK
    Leukemia 26:1462-70. 2012
    ....
  28. ncbi request reprint Inhibiting the phosphoinositide 3-kinase pathway for cancer treatment
    P Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, U K
    Biochem Soc Trans 32:393-6. 2004
    ..Prototype inhibitors show evidence of anticancer activity in vitro and in vivo animal models. The recent development of isoform-selective inhibitors shows considerable promise for cancer treatment...
  29. doi request reprint From darkness to light with biomarkers in early clinical trials of cancer drugs
    C P Carden
    The Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, UK
    Clin Pharmacol Ther 85:131-3. 2009
    ....
  30. pmc The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations
    M O Leach
    Cancer Research UK Clinical Magnetic Resonance Research Group, Institute of Cancer Research, Royal Marsden Hospital, Sutton, Surrey, UK
    Br J Cancer 92:1599-610. 2005
    ..This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used...
  31. ncbi request reprint Evaluation of the cassette dosing approach for assessing the pharmacokinetics of geldanamycin analogues in mice
    N F Smith
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, SM2 5NG, Sutton, UK
    Cancer Chemother Pharmacol 54:475-86. 2004
    ..Studies were performed to assess whether cassette dosing, the coadministration of several compounds to a single animal, is a suitable approach to evaluate the preclinical pharmacokinetics of geldanamycin analogues in high throughput...
  32. ncbi request reprint High-throughput screening for identification of small molecule inhibitors of histone acetyltransferases using scintillating microplates (FlashPlate)
    F Turlais
    CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, United Kingdom
    Anal Biochem 298:62-8. 2001
    ..This resulted in a simple "mix and measure" assay that is currently being used for the identification of HAT inhibitors...
  33. pmc A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points
    A O'DONNELL
    Institute of Cancer Research, and Royal Marsden Hospital, Sutton SM2 5PT, UK
    Br J Cancer 93:876-83. 2005
    ..The 145 mg m-2 dose level is thus the recommended dose for future study...
  34. ncbi request reprint Measurement of tumor oxygenation: in vivo comparison of a luminescence fiber-optic sensor and a polarographic electrode in the p22 tumor
    B M Seddon
    CRC Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5PT, United Kingdom
    Radiat Res 155:837-46. 2001
    ..6 to 28.1 mm hg...
  35. ncbi request reprint Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues
    Swee Y Sharp
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom
    Mol Cancer Ther 6:1198-211. 2007
    ..The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors...
  36. ncbi request reprint Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin
    Alison Maloney
    Haddow Laboratories, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey, United Kingdom
    Cancer Res 67:3239-53. 2007
    ....
  37. ncbi request reprint Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors
    Masahiko Hayakawa
    Institute for Drug Discovery Research, Astellas Pharma Inc, 5 2 3 Tokodai, Tsukuba, Ibaraki 300 2698, Japan
    Bioorg Med Chem 15:403-12. 2007
    ..21microM, respectively, and suppressed tumor growth by 37% in a mouse HeLa xenograft model when dosed intraperitoneally at 25mg/kg. These results suggest that selective p110alpha inhibitors may have potential as cancer therapeutic agents...
  38. ncbi request reprint Synthesis and biological evaluation of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors
    Masahiko Hayakawa
    Drug Discovery Research, Astellas Pharma Inc, 5 2 3 Tokodai, Tsukuba, Ibaraki 300 2698, Japan
    Bioorg Med Chem Lett 17:2438-42. 2007
    ..Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice...
  39. ncbi request reprint Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors
    Marissa V Powers
    Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, Haddow Laboratories, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
    Endocr Relat Cancer 13:S125-35. 2006
    ..We also review the discovery and development of novel small-molecule inhibitors and discuss alternative approaches to inhibit HSP90 activity, both of which offer exciting prospects for the future...
  40. ncbi request reprint The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery
    Nicola F Smith
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom
    Mol Cancer Ther 6:428-40. 2007
    ..Subject to critical analysis and validation in each case, the use of cassette dosing is recommended in appropriate chemical series to enhance the efficiency of drug discovery and reduce animal usage...
  41. ncbi request reprint Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol
    Nicolas Proisy
    School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom
    Chem Biol 13:1203-15. 2006
    ..e., depletion of client proteins with upregulation of Hsp70...
  42. ncbi request reprint In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors
    Swee Y Sharp
    Haddow Laboratories, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, UK
    Cancer Res 67:2206-16. 2007
    ..g., aqueous solubility, independence from NQO1 and P-glycoprotein). These compounds form the basis for further structure-based optimization to identify more potent inhibitors suitable for clinical development...
  43. ncbi request reprint New approaches to molecular cancer therapeutics
    Ian Collins
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Nat Chem Biol 2:689-700. 2006
    ..We show how chemical biology approaches offer techniques for interconnecting elements of the traditional linear progression from gene to drug, thereby providing a basis for increasing speed and success in cancer drug discovery...
  44. ncbi request reprint In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography
    Julius Leyton
    Molecular Therapy and Cancer Cell Biology, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom
    Cancer Res 66:7621-9. 2006
    ..Drug-induced changes in tumor [18F]FLT uptake were due, at least in part, to reductions in TK1 transcription and translation...
  45. ncbi request reprint Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey UK
    Ann N Y Acad Sci 1113:202-16. 2007
    ..We stress how basic and translational research has been mutually beneficial and indicate future directions to enhance our understanding of molecular chaperones and their exploitation in cancer and other diseases...
  46. doi request reprint Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901
    Julius Leyton
    Molecular Therapy Group, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom
    Mol Cancer Ther 7:3112-21. 2008
    ..6; P > or = 0.003). In summary, [18F]FLT-PET is a sensitive imaging biomarker for detecting the antiproliferative effect of MEK1/2 inhibition by PD0325901...
  47. doi request reprint Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis
    Marissa V Powers
    Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, UK
    Cancer Cell 14:250-62. 2008
    ..Importantly, simultaneous silencing of HSP70 isoforms in nontumorigenic cell lines does not result in comparable growth arrest or induction of apoptosis, indicating a potential therapeutic window...
  48. doi request reprint The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer
    Adrian J Folkes
    Piramed Pharma, 957 Buckingham Avenue, Slough, Berks SL1 4NL, United Kingdom
    J Med Chem 51:5522-32. 2008
    ..This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer...
  49. doi request reprint Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration
    John J Caldwell
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, U K
    J Med Chem 51:2147-57. 2008
    ..Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera...
  50. doi request reprint Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin
    Joanna L Holmes
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom
    Cancer Res 68:1188-97. 2008
    ..Furthermore, AHA1 knockdown could sensitize cancer cells to 17-AAG. We conclude that modulation of AHA1 might be a potential therapeutic strategy to increase sensitivity to HSP90 inhibitors...
  51. ncbi request reprint Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity
    Florence Chan
    Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK, 15 Cotswold Road, Belmont, Surrey SM2 5NG, United Kingdom
    Mol Cancer Ther 6:3147-57. 2007
    ..This has facilitated the use of 3'-deoxy-3'[(18)F]fluorothymidine-positron emission tomography to measure noninvasively the biological activity of the Aurora kinase inhibitor CCT129202 in vivo...
  52. ncbi request reprint The cyclin-dependent kinase inhibitor seliciclib (R-roscovitine; CYC202) decreases the expression of mitotic control genes and prevents entry into mitosis
    Steven R Whittaker
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK
    Cell Cycle 6:3114-31. 2007
    ....
  53. ncbi request reprint 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer
    Paul A Brough
    Vernalis Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, U K p brough vernalis com
    J Med Chem 51:196-218. 2008
    ..Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%...
  54. ncbi request reprint AHR- and DNA-damage-mediated gene expression responses induced by benzo(a)pyrene in human cell lines
    Sarah L Hockley
    Section of Molecular Carcinogenesis, The Institute of Cancer Research, Surrey, UK
    Chem Res Toxicol 20:1797-810. 2007
    ..Promoter analysis identified candidate genes for direct transcriptional regulation by either AHR or p53. These analyses have further dissected and characterized the complex cellular response to BaP...
  55. ncbi request reprint Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts
    Sharon M Gowan
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK
    Assay Drug Dev Technol 5:391-401. 2007
    ..This optimized procedure can be used for both in vitro and in vivo analysis, unlike an established fixed-cell ELISA with a time-resolved fluorescent end point...
  56. ncbi request reprint Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors
    Masahiko Hayakawa
    Drug Discovery Research, Astellas Pharma Inc, 5 2 3 Tokodai, Tsukuba, Ibaraki, Japan
    Bioorg Med Chem 15:5837-44. 2007
    ..26 nM, respectively; to the best of our knowledge, these compounds are the most potent PI3K p110alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo...
  57. ncbi request reprint Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases
    Florence I Raynaud
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow and McElwain Laboratories, Sutton, Surrey, United Kingdom
    Cancer Res 67:5840-50. 2007
    ....
  58. ncbi request reprint A duplexed phenotypic screen for the simultaneous detection of inhibitors of the molecular chaperone heat shock protein 90 and modulators of cellular acetylation
    Anthea Hardcastle
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom
    Mol Cancer Ther 6:1112-22. 2007
    ..In the acetylation arm, two compounds increased cellular acetylation, one of which inhibited histone deacetylase activity. A third compound decreased cellular histone acetylation, potentially through a novel mechanism of action...
  59. ncbi request reprint Inhibitors of the HSP90 molecular chaperone: current status
    Swee Sharp
    Signal Transduction and Molecular Pharmacology Team, Cancer Research UK, Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, SM2 5NG, United Kingdom
    Adv Cancer Res 95:323-48. 2006
    ..Thus, it is not surprising that new HSP90 agents are under development against this novel target for cancer therapy and several show promise...
  60. ncbi request reprint Magnetic resonance spectroscopy monitoring of mitogen-activated protein kinase signaling inhibition
    Mounia Beloueche-Babari
    Cancer Research UK Clinical Magnetic Resonance Research Group, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK
    Cancer Res 65:3356-63. 2005
    ..Thus, phosphocholine has potential as a noninvasive pharmacodynamic marker for monitoring MAPK signaling blockade...
  61. ncbi request reprint Gene expression microarray technologies in the development of new therapeutic agents
    Paul A Clarke
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, UK
    Eur J Cancer 40:2560-91. 2004
    ..The approach can identify on-target and off-target effects. It can be used to identify molecular biomarkers for proof of concept studies, pharmacodynamic endpoints and prognostic markers for predicting outcome and patient selection...
  62. ncbi request reprint Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms
    Lisa Wright
    Vernalis R and D Ltd, Granta Park, Abington, Cambridge CB1 6GB, UK
    Chem Biol 11:775-85. 2004
    ....
  63. ncbi request reprint Histone modification enzymes: novel targets for cancer drugs
    Rebecca Kristeleit
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK
    Expert Opin Emerg Drugs 9:135-54. 2004
    ..It is likely that many of the enzymes involved in the control of histone modification will provide therapeutic opportunities for the treatment of cancer, including histone methyltransferases and Aurora kinases...
  64. ncbi request reprint Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK
    Cancer Lett 206:149-57. 2004
    ..This article reviews the current status and future prospects for the exploitation of Hsp90 as a new molecular target for cancer treatment...
  65. ncbi request reprint Strategies for treating cancers caused by multiple genome abnormalities: from concepts to cures?
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
    Curr Opin Investig Drugs 4:1410-5. 2003
    ..g., imatinib in chronic myeloid leukemia and gastrointestinal stromal tumors. Other multigenic cancers will require drug cocktails or single drugs acting on multiple downstream targets...
  66. ncbi request reprint The Cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway
    Steven R Whittaker
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, United Kingdom
    Cancer Res 64:262-72. 2004
    ..In addition to providing useful insights into the molecular pharmacology of CYC202 in human cancer cells, the results also suggest potential pharmacodynamic end points for use in clinical trials with the drug...
  67. ncbi request reprint Magnetic resonance spectroscopic pharmacodynamic markers of the heat shock protein 90 inhibitor 17-allylamino,17-demethoxygeldanamycin (17AAG) in human colon cancer models
    Yuen Li Chung
    Cancer Research UK Biomedical Magnetic Resonance Research Group, Department of Basic Medical Sciences, St George s Hospital Medical School, London, UK
    J Natl Cancer Inst 95:1624-33. 2003
    ..We used phosphorus magnetic resonance spectroscopy (31P-MRS) to determine whether 17AAG treatment leads to alterations in phospholipids that could serve as pharmacodynamic markers for tumor response to 17AAG...
  68. ncbi request reprint The contemporary drug development process: advances and challenges in preclinical and clinical development
    Michelle D Garrett
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, U K
    Prog Cell Cycle Res 5:145-58. 2003
    ..However, many of the concepts, approaches and issues are generally common to other therapeutic areas...
  69. ncbi request reprint The opportunities and challenges of personalized genome-based molecular therapies for cancer: targets, technologies, and molecular chaperones
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SN2 5NG, UK
    Cancer Chemother Pharmacol 52:S45-56. 2003
    ....
  70. ncbi request reprint Cancer genome targets: RAF-ing up tumor cells to overcome oncogene addiction
    Paul Workman
    Expert Rev Anticancer Ther 2:611-4. 2002
  71. ncbi request reprint ErbB2 overexpression in an ovarian cancer cell line confers sensitivity to the HSP90 inhibitor geldanamycin
    Vicki Smith
    CRC Center for Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK
    Anticancer Res 22:1993-9. 2002
    ..These data suggest that erbB2 status in ovarian cancr may contribute to chemosensitivity, in some cases leading to increased sensitivity (as with geldanamycin) but in other cases leading to resistance (as with cisplatin)...
  72. ncbi request reprint Validation of the fluorinated 2-nitroimidazole SR-4554 as a noninvasive hypoxia marker detected by magnetic resonance spectroscopy
    Beatrice M Seddon
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
    Clin Cancer Res 8:2323-35. 2002
    ..We present validation studies of SR-4554 as a noninvasive hypoxia marker detected by fluorine-19 magnetic resonance spectroscopy ((19)F MRS) in the P22 carcinosarcoma, a tumor with clinically relevant hypoxia levels...
  73. ncbi request reprint Establishment and characterization of acquired resistance to the farnesyl protein transferase inhibitor R115777 in a human colon cancer cell line
    Victoria Smith
    CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton SM2 5NG, UK
    Clin Cancer Res 8:2002-9. 2002
    ..The results suggest that the development of clinical resistance may occur with farnesyl protein transferase inhibitors...
  74. ncbi request reprint Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors
    Noan Minh Chau
    Cell Growth Regulation and Angiogenesis Team, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom
    Cancer Res 65:4918-28. 2005
    ..Our cell-based assay approach has successfully identified novel compounds that differentially target hypoxia and/or growth factor-mediated induction of HIF-1alpha...
  75. ncbi request reprint The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors
    Kwai Ming J Cheung
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK and Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    Bioorg Med Chem Lett 15:3338-43. 2005
    ..Some initial structure-activity relationships are discussed, as well as the crystal structure of CCT018159 bound to Hsp90...
  76. ncbi request reprint Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies
    Udai Banerji
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, Surrey SM2 5NG, UK
    J Clin Oncol 23:4152-61. 2005
    ..To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials...
  77. ncbi request reprint Inhibitors of the HSP90 molecular chaperone: attacking the master regulator in cancer
    Edward McDonald
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK
    Curr Top Med Chem 6:1091-107. 2006
    ..Medicinal chemists have used this information to develop high affinity lead compounds. Recent research provides the platform for exciting developments in the area of HSP90 inhibition over the next few years...
  78. ncbi request reprint Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors
    Masahiko Hayakawa
    Institute for Drug Discovery Research, Astellas Pharma Inc, Tsukuba, Ibaraki 300 2698, Japan
    Bioorg Med Chem 14:6847-58. 2006
    ..58 microM. Moreover, 15e was found to be selective for p110alpha over other PI3K isoforms and protein kinases, making it the first example of a selective PI3K p110alpha inhibitor...
  79. ncbi request reprint Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT
    Nivedita Sain
    The Haddow Laboratories, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom
    Mol Cancer Ther 5:1197-208. 2006
    ..In conclusion, 17-AAG may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by ERBB2 and/or p-AKT...
  80. ncbi request reprint Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK
    J Natl Cancer Inst 98:580-98. 2006
    ..Development, validation, and implementation of minimally invasive PK/PD methods are encouraged...
  81. ncbi request reprint Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis
    Sharon Sanderson
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey, United Kingdom
    Mol Cancer Ther 5:522-32. 2006
    ....
  82. ncbi request reprint 4-Amino derivatives of the Hsp90 inhibitor CCT018159
    Xavier Barril
    Vernalis Ltd, Granta Park, Cambridge CB1 6GB, UK
    Bioorg Med Chem Lett 16:2543-8. 2006
    ....
  83. ncbi request reprint Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models
    Nada M S Al-Saffar
    Cancer Research UK Clinical Magnetic Resonance Research Group, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom
    Cancer Res 66:427-34. 2006
    ..The decrease in phosphocholine, total choline, and phosphomonoesters may have potential as noninvasive pharmacodynamic biomarkers for determining tumor response following treatment with choline kinase inhibitors...
  84. ncbi request reprint Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity
    Lindsay Stimson
    Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom
    Mol Cancer Ther 4:1521-32. 2005
    ..As one of the first series of small-molecule inhibitors of HAT activity, further analogue synthesis is being pursued to examine the potential scope for reducing chemical reactivity while maintaining HAT inhibition...
  85. ncbi request reprint Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models
    Udai Banerji
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, United Kingdom
    Clin Cancer Res 11:7023-32. 2005
    ..To establish the pharmacokinetic and pharmacodynamic profile of the heat shock protein 90 (HSP90) inhibitor 17-allylamino, 17-demethoxygeldanamycin (17-AAG) in ovarian cancer xenograft models...
  86. 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...
  87. ncbi request reprint A liquid chromatographic-tandem mass spectrometric method for the determination of two selective thymidylate synthase inhibitors, BGC945 and BGC638, in mouse plasma
    Nadya Wood
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
    J Chromatogr B Analyt Technol Biomed Life Sci 824:181-8. 2005
    ..This validated method has been used to define the first pharmacokinetic report of BGC945 and BGC638 in mice...
  88. ncbi request reprint In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202
    Florence I Raynaud
    Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Haddow Laboratories, Belmont, Sutton, United Kingdom
    Clin Cancer Res 11:4875-87. 2005
    ..To investigate pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine, and CYC202 (R-roscovitine; seliciclib) in the HCT116 human colon carcinoma model...
  89. ncbi request reprint Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design
    Brian W Dymock
    Vernalis Ltd, Granta Park, Great Abington, Cambridge, UK
    J Med Chem 48:4212-5. 2005
    ..These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG...
  90. ncbi request reprint Solid-phase immunoassays in mechanism-based drug discovery: their application in the development of inhibitors of the molecular chaperone heat-shock protein 90
    Anthea Hardcastle
    Haddow Laboratories, Cancer Research UK Centre for Cancer Therapeutics at Institute of Cancer Research, Sutton, Surrey, UK
    Assay Drug Dev Technol 3:273-85. 2005
    ..Finally, comparison is made between the use and applicability of this type of immunoassay and other techniques such as western blotting, immunohistochemistry, and flow cytometry analysis...
  91. ncbi request reprint Assays for the identification and evaluation of histone acetyltransferase inhibitors
    G Wynne Aherne
    Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK
    Methods 26:245-53. 2002
    ..This latter method provides a medium-throughput alternative to the use of immunoblotting for mechanistic studies...