Paul Bamborough

Summary

Affiliation: GlaxoSmithKline Research and Development
Country: USA

Publications

  1. ncbi request reprint Potent small molecule inhibitors of spleen tyrosine kinase (Syk)
    Justine Y Q Lai
    Aventis Pharmaceuticals, Route 202 206, Brigdewater, NJ 08807, USA
    Bioorg Med Chem Lett 13:3111-4. 2003
  2. ncbi request reprint 5-(1H-Benzimidazol-1-yl)-3-alkoxy-2-thiophenecarbonitriles as potent, selective, inhibitors of IKK-epsilon kinase
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 16:6236-40. 2006
  3. ncbi request reprint The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta kinases
    John A Christopher
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 17:3972-7. 2007
  4. ncbi request reprint N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 17:4363-8. 2007
  5. doi request reprint Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes
    Richard M Angell
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 18:4433-7. 2008
  6. doi request reprint System-based drug discovery within the human kinome
    Paul Bamborough
    Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Stevenage, UK
    Expert Opin Drug Discov 7:1053-70. 2012
  7. doi request reprint Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides
    Paul Bamborough
    Epinova DPU, Immuno Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    J Med Chem 55:587-96. 2012
  8. doi request reprint Selectivity of kinase inhibitor fragments
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
    J Med Chem 54:5131-43. 2011
  9. doi request reprint Targeting IKKβ for the treatment of rheumatoid arthritis
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Stevenage, Hertfordshire, UK
    Drug News Perspect 23:483-90. 2010
  10. ncbi request reprint Progress towards the development of anti-inflammatory inhibitors of IKKbeta
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Curr Top Med Chem 9:623-39. 2009

Collaborators

Detail Information

Publications27

  1. ncbi request reprint Potent small molecule inhibitors of spleen tyrosine kinase (Syk)
    Justine Y Q Lai
    Aventis Pharmaceuticals, Route 202 206, Brigdewater, NJ 08807, USA
    Bioorg Med Chem Lett 13:3111-4. 2003
    ..The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM)...
  2. ncbi request reprint 5-(1H-Benzimidazol-1-yl)-3-alkoxy-2-thiophenecarbonitriles as potent, selective, inhibitors of IKK-epsilon kinase
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 16:6236-40. 2006
    ..Compound 12e was identified with an IKK-epsilon enzyme potency of pIC(50) 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family...
  3. ncbi request reprint The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta kinases
    John A Christopher
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 17:3972-7. 2007
    ..The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance...
  4. ncbi request reprint N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 17:4363-8. 2007
    ..Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties...
  5. doi request reprint Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes
    Richard M Angell
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 18:4433-7. 2008
    ..Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound...
  6. doi request reprint System-based drug discovery within the human kinome
    Paul Bamborough
    Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Stevenage, UK
    Expert Opin Drug Discov 7:1053-70. 2012
    ..This is increasingly translating into success in the clinic, with five new kinase inhibitor drugs approved since 2011. However, despite encouraging signs in other areas, success has been largely restricted to oncology...
  7. doi request reprint Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides
    Paul Bamborough
    Epinova DPU, Immuno Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    J Med Chem 55:587-96. 2012
    ..This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization...
  8. doi request reprint Selectivity of kinase inhibitor fragments
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
    J Med Chem 54:5131-43. 2011
    ..Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases...
  9. doi request reprint Targeting IKKβ for the treatment of rheumatoid arthritis
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Stevenage, Hertfordshire, UK
    Drug News Perspect 23:483-90. 2010
    ..Inhibitors of the kinase activity of IKKβ offer opportunities for intervention in RA, as well as other inflammatory disorders. Some examples for which the most extensive data are available will here be reviewed...
  10. ncbi request reprint Progress towards the development of anti-inflammatory inhibitors of IKKbeta
    Paul Bamborough
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Curr Top Med Chem 9:623-39. 2009
    ..Here, we will review the literature describing small molecule inhibitors of IKKbeta (IKK2), the most widely studied of the IKKs...
  11. doi request reprint Assessment of chemical coverage of kinome space and its implications for kinase drug discovery
    Paul Bamborough
    Molecular Discovery Research, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
    J Med Chem 51:7898-914. 2008
    ..Taken together, these results show how broad cross-profiling can provide important insights to assist kinase drug discovery...
  12. doi request reprint 4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors
    John Liddle
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK
    Bioorg Med Chem Lett 19:2504-8. 2009
    ..The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity...
  13. doi request reprint Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity
    Richard Angell
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 18:4428-32. 2008
    ..The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode...
  14. doi request reprint 3,5-Disubstituted-indole-7-carboxamides: the discovery of a novel series of potent, selective inhibitors of IKK-β
    David D Miller
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 21:2255-8. 2011
    ..Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles...
  15. doi request reprint Kinase array design, back to front: biaryl amides
    Ian Baldwin
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 18:5285-9. 2008
    ..Results are shown for p38alpha and cFMS kinase, for which multiple distinct series with nanomolar potency were discovered. Some of the compounds showed potency in cell-based assays and good pharmacokinetic properties...
  16. doi request reprint p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression
    Nicola M Aston
    GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Rd, Stevenage, Hertfordshire SG1 2NY, UK
    J Med Chem 52:6257-69. 2009
    ....
  17. ncbi request reprint Biphenyl amide p38 kinase inhibitors 1: Discovery and binding mode
    Richard M Angell
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 18:318-23. 2008
    ..The discovery of the series through structure-based focused screening is described, and the binding mode of the compounds is explained with reference to X-ray crystal structures...
  18. doi request reprint 4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy
    John Liddle
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 22:5222-6. 2012
    ..Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation...
  19. doi request reprint The discovery and initial optimisation of pyrrole-2-carboxamides as inhibitors of p38alpha MAP kinase
    Kenneth Down
    GlaxoSmithKline R and D, Medicines Research Centre, Stevenage, Hertfordshire, UK
    Bioorg Med Chem Lett 20:3936-40. 2010
    ..Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies...
  20. doi request reprint Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery
    Chun wa Chung
    Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    J Med Chem 55:576-86. 2012
    ..An important implication is that the bromodomains are not only a phylogenetic family but also a system in which chemical and structural knowledge of one bromodomain gives insights transferrable to others...
  21. ncbi request reprint Biphenyl amide p38 kinase inhibitors 2: Optimisation and SAR
    Richard M Angell
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
    Bioorg Med Chem Lett 18:324-8. 2008
    ..Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model...
  22. doi request reprint Discovery of 6-aryl-7-alkoxyisoquinoline inhibitors of IkappaB kinase-beta (IKK-beta)
    John A Christopher
    GlaxoSmithKline R and D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
    J Med Chem 52:3098-102. 2009
    ....
  23. doi request reprint Discovery and characterization of small molecule inhibitors of the BET family bromodomains
    Chun wa Chung
    Molecular Discovery Research, GlaxoSmithKline R and D, Stevenage SG5 4HT, UK
    J Med Chem 54:3827-38. 2011
    ..X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity...
  24. doi request reprint Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A)
    Jonathan Seal
    Epinova DPU, GlaxoSmithKline R and D, Medicines Research Centre, Stevenage, Hertfordshire, UK
    Bioorg Med Chem Lett 22:2968-72. 2012
    ..One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model...
  25. doi request reprint GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor
    Alastair D Reith
    External Alliances and Development, R and D China, GlaxoSmithKline Pharmaceuticals R and D, Stevenage, UK
    Bioorg Med Chem Lett 22:5625-9. 2012
    ..3-1.0 μM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg...
  26. ncbi request reprint Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease
    Martin J Slater
    GlaxoSmithKline Medicines Research Center, Gunnels Wood Road, Stevenage, SG1 2NY, UK
    Org Lett 5:4627-30. 2003
    ..Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay...
  27. ncbi request reprint Mapping the kinase domain of Janus Kinase 3
    Christopher Adams
    Aventis Pharmaceuticals, 1041 Route 202 206, PO Box 6800, Bridgewater, NJ 08807, USA
    Bioorg Med Chem Lett 13:3105-10. 2003
    ..The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed...