Genomes and Genes
James R Burke
Affiliation: Bristol-Myers Squibb
- Targeting I kappa B kinase for the treatment of inflammatory and other disordersJames R Burke
Bristol Myers Squibb Pharmaceutical Research Institute, Immunology, Inflammation and Pulmonary Drug Discovery, PO Box 4000, Route 206 and Provinceline Road, Princeton, NJ 08543, USA
Curr Opin Drug Discov Devel 6:720-8. 2003..Potential mechanism-based toxicities will also be discussed...
- Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and -epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK-2J R Burke
Drug Discovery Research, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
J Biol Chem 274:36146-52. 1999..Therefore, the C terminus of IkappaB-alpha is important in activating the msIKK through interactions with subunits other than the IKK-2...
- Targeting phospholipase A2 for the treatment of inflammatory skin diseasesJ R Burke
Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
Curr Opin Investig Drugs 2:1549-52. 2001..In this review, the characteristics and promise of PLA, inhibitors, which have shown activity in preclinical models of skin inflammation are discussed along with the challenges the field faces in developing clinical candidates...
- The catalytic subunits of IkappaB kinase, IKK-1 and IKK-2, contain non-equivalent active sites when expressed as homodimersJames R Burke
Drug Discovery and Exploratory Development, Bristol Myers Squibb Pharmaceutical Research Institute, P O Box 4000, Princeton, NJ 08543, USA
Biochem Biophys Res Commun 293:1508-13. 2002..In addition, the two active sites within the dimer appear to act in a cooperative fashion so that binding of peptide inhibitor at one active site affects the conformation of the other active site...
- BMS-229724 is a tight-binding inhibitor of cytosolic phospholipase A2 that acts at the lipid/water interface and possesses anti-inflammatory activity in skin inflammation modelsJ R Burke
Dermatology Drug Discovery, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
J Pharmacol Exp Ther 298:376-85. 2001..In hairless guinea pigs, BMS-229724 was active orally (10 mg/kg) in a UVB-induced skin erythema model in hairless guinea pigs...
- BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in miceJames R Burke
Department of Immunology, Inflammation and Pulmonary Drug Discovery, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
J Biol Chem 278:1450-6. 2003..Thus, the compound is effective against NF-kappa B activation in mice and represents an important tool for investigating the role of IKK in disease models...
- Periodic, partial inhibition of IkappaB Kinase beta-mediated signaling yields therapeutic benefit in preclinical models of rheumatoid arthritisKathleen M Gillooly
Departments of Immunology and Inflammation Drug Discovery, Bristol Myers Squibb Research and Development, Princeton, New Jersey, USA
J Pharmacol Exp Ther 331:349-60. 2009..Thus, only partial and transient inhibition of IKKbeta is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKKbeta inhibitors...
- Novel tricyclic inhibitors of IKK2: discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)Scott H Watterson
Bristol Myers Squibb Research and Development, Princeton, NJ 08543 4000, USA
Bioorg Med Chem Lett 21:7006-12. 2011..Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease...
- Imidazo[4,5-d]thiazolo[5,4-b]pyridine based inhibitors of IKK2: synthesis, SAR, PK/PD and activity in a preclinical model of rheumatoid arthritisAlaric J Dyckman
Bristol Myers Squibb, Research and Development, Princeton, NJ 08543 4000, USA
Bioorg Med Chem Lett 21:383-6. 2011..The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis...
- Novel tricyclic inhibitors of IkappaB kinaseJames Kempson
Departments of Discovery Chemistry, Discovery Biology, and Metabolism and Pharmacokinetics and Synthesis and Analysis Technology Team, Bristol Myers Squibb Research and Development, Princeton, New Jersey 08543 4000, USA
J Med Chem 52:1994-2005. 2009..This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation...
- A highly selective inhibitor of IkappaB kinase, BMS-345541, augments graft survival mediated by suboptimal immunosuppression in a murine model of cardiac graft rejectionRobert M Townsend
Department of Immunology, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
Transplantation 77:1090-4. 2004..These results indicate that a potent IKK inhibitor may have the potential of being a novel therapeutic agent for the prevention of graft rejection...
- NEMO binding domain of IKK-2 encompasses amino acids 735-745Joann Strnad
Drug Discovery Research, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
J Mol Recognit 19:227-33. 2006..These longer NBD-containing peptides may be required to give the NBD an appropriate conformation for recognition by NEMO and/or to provide for additional interactions with NEMO...
- A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in miceKim W McIntyre
Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
Arthritis Rheum 48:2652-9. 2003....
- Collagen and aggrecan degradation is blocked in interleukin-1-treated cartilage explants by an inhibitor of IkappaB kinase through suppression of metalloproteinase expressionMark A Pattoli
Immunology, Inflammation, and Pulmonary Drug Discovery, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
J Pharmacol Exp Ther 315:382-8. 2005....
- Small Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-9351George V De Lucca
Immunosciences Discovery Chemistry, Immunoscience Discovery Biology, Molecular Structure and Design, Molecular Discovery Technologies, Metabolism and Pharmacokinetic Department, Pharmaceutical Candidate Optimization, and ECTR CTTO Imaging Department, Bristol Myers Squibb Research and Development, P O Box 4000, Princeton, New Jersey 08543, United States
J Med Chem 59:7915-35. 2016....
- Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitorsFrancis Beaulieu
Bristol Myers Squibb Pharmaceutical Research Institute, 100 boul de l Industrie, Candiac, Que, Canada J5R 1J1
Bioorg Med Chem Lett 17:1233-7. 2007..The synthesis and biological activities of these potent IKK inhibitors are described...
- Synthesis and structure-activity relationship of imidazo(1,2-a)thieno(3,2-e)pyrazines as IKK-beta inhibitorsMakonen Belema
Bristol Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Bioorg Med Chem Lett 17:4284-9. 2007..The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described...
- Synthesis, initial SAR and biological evaluation of 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine derived inhibitors of IkappaB kinaseJames Kempson
Bristol Myers Squibb Research and Development, Princeton, NJ 08543 4000, USA
Bioorg Med Chem Lett 19:2646-9. 2009..A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure-activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS...
- IkappaB kinase inhibitors for treating autoimmune and inflammatory disorders: potential and challengesJoann Strnad
Immunology and Inflammation Drug Discovery, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
Trends Pharmacol Sci 28:142-8. 2007..It is still unclear what toxicities will be associated with IKK inhibitors; a discussion of the potential for mechanism-based toxicities such as teratogenicity, lymphopoietic defects and susceptibility to infection is also presented...
- Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTScott H Watterson
Bristol Myers Squibb Research and Development, P O Box 4000, Princeton, New Jersey 08543, United States
J Med Chem 59:9173-9200. 2016..With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies...
- Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseasesQing Shi
Bristol Myers Squibb Research and Development, P O Box 4000, Princeton, NJ 08543 4000, United States Electronic address
Bioorg Med Chem Lett 24:2206-11. 2014..Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development...
- Cytosolic phospholipase A2 shows burst kinetics consistent with the slow, reversible formation of a dead-end complexMatthew G Guenther
Drug Discovery and Exploratory Development, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA
Arch Biochem Biophys 398:101-8. 2002..This may provide a means by which the enzyme is switched off after a few hundred turnovers in order to prevent unabated phospholipid hydrolysis in cells which may be deleterious to membrane integrity...
- Duration and intensity of NF-kappaB activity determine the severity of endotoxin-induced acute lung injuryM Brett Everhart
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
J Immunol 176:4995-5005. 2006..Therefore, sustained NF-kappaB activation correlates with severity of lung injury, and interdiction in the NF-kappaB pathway is beneficial even after the onset of lung inflammation...
- BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathwaysJinming Yang
Veterans Affairs Medical Center and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
Clin Cancer Res 12:950-60. 2006..We explored the possibility of exploiting IKK as a therapeutic target in melanoma by using BMS-345541, a novel compound with a highly selective IKKbeta inhibitory activity, to trigger melanoma cell apoptosis...
- Disruption of the toxic conformation of the expanded polyglutamine stretch leads to suppression of aggregate formation and cytotoxicityHelena A Popiel
Division of Functional Genomics, Department of Post Genomics and Diseases, Osaka University Graduate School of Medicine, 2 2 B9 Yamadaoka, Suita, Osaka, Japan
Biochem Biophys Res Commun 317:1200-6. 2004..These results show that a gain in toxic conformation of the expanded polyQ protein is essential for aggregation and cytotoxicity, providing insight into establishing therapies against the polyQ diseases...
- IKK mediates ischemia-induced neuronal deathOliver Herrmann
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
Nat Med 11:1322-9. 2005..5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy...
- Polyglutamine expansion inhibits respiration by increasing reactive oxygen species in isolated mitochondriaKasturi L Puranam
Deane Laboratory, Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA
Biochem Biophys Res Commun 341:607-13. 2006..We propose a model in which pathologic-length PolyQ protein directly inhibits mitochondrial function by inducing oxidative stress...
- Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug librariesThung S Lai
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
Chem Biol 15:969-78. 2008..The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases...
- Optimization of a polyglutamine aggregation inhibitor peptide (QBP1) using a thioflavin T fluorescence assayLora Hamuro
Provid Pharmaceuticals, Inc, North Brunswick, NJ 08902, USA
Assay Drug Dev Technol 5:629-36. 2007..The assay detected activities that differed by three orders of magnitudes with Z' = 0.56, which is suitable for high-throughput screening and allowed us to do lead optimization of QBP1 analogs for pharmacophore model building...
- Phage display screening for peptides that inhibit polyglutamine aggregationDaniel J Kenan
Duke University Medical Center, Department of Medicine Neurology and Deane Laboratory, Durham, North Carolina, USA
Methods Enzymol 413:253-73. 2006..A similar experimental approach could be used for other diseases caused by conformational change in disease proteins, including prion, Alzheimer's, and Parkinson's diseases...