Nrf2, a master regulator of the phase II gene response to stress, is kept at low concentrations in the cell through binding to Keap1, an adaptor protein for the Cul3 ubiquitin ligase complex. To identify Nrf2 activators, two separate time-resolved fluorescence resonance energy transfer (TR-FRET) assays were developed to monitor the binding of Nrf2-Keap1 and Cul3-Keap1, respectively. The triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im) and its analogs, exhibited approximately 100-fold better potency in the Cul3-Keap1 assay than in the Nrf2-Keap1 assay, and this difference was more profound at 37 degrees C than at room temperature in the Nrf2-Keap1 assay, but this phenomenon was not observed in the Cul3-Keap1 assay. A full diversity screen of approximately 2,200,000 GSK compounds was run with the Cul3-Keap1 TR-FRET assay and multiple chemical series were identified and characterized.
机构:
Rutgers State Univ, Dept Med Chem, Ernest Mario Sch Pharm, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USARutgers State Univ, Dept Med Chem, Ernest Mario Sch Pharm, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USA
Lee, Sumi
Abed, Dhulfiqar Ali
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Rutgers State Univ, Dept Med Chem, Ernest Mario Sch Pharm, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USARutgers State Univ, Dept Med Chem, Ernest Mario Sch Pharm, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USA
Abed, Dhulfiqar Ali
Beamer, Lesa J.
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Univ Missouri, Dept Biochem, Columbia, MO USARutgers State Univ, Dept Med Chem, Ernest Mario Sch Pharm, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USA
Beamer, Lesa J.
Hu, Longqin
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Rutgers State Univ, Dept Med Chem, Ernest Mario Sch Pharm, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USA
Rutgers Canc Inst New Jersey, New Brunswick, NJ USARutgers State Univ, Dept Med Chem, Ernest Mario Sch Pharm, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USA
机构:Ankara Univ, Fac Sci, Tissue Engn Biomat & Nanobiotechnol Lab, TR-06100 Ankara, Turkey
Ergin, Ekin
Dogan, Arin
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机构:Ankara Univ, Fac Sci, Tissue Engn Biomat & Nanobiotechnol Lab, TR-06100 Ankara, Turkey
Dogan, Arin
Parmaksiz, Mahmut
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机构:Ankara Univ, Fac Sci, Tissue Engn Biomat & Nanobiotechnol Lab, TR-06100 Ankara, Turkey
Parmaksiz, Mahmut
Elcin, Ayse E.
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机构:Ankara Univ, Fac Sci, Tissue Engn Biomat & Nanobiotechnol Lab, TR-06100 Ankara, Turkey
Elcin, Ayse E.
Elcin, Yasar M.
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Ankara Univ, Fac Sci, Tissue Engn Biomat & Nanobiotechnol Lab, TR-06100 Ankara, Turkey
Ankara Univ, Stem Cell Inst, Ankara, TurkeyAnkara Univ, Fac Sci, Tissue Engn Biomat & Nanobiotechnol Lab, TR-06100 Ankara, Turkey
机构:
Mol Imaging Innovat Inst MI3, Dept Radiol, Weill Cornell Med, New York, NY 10065 USA
Mansoura Univ, Fac Pharm, Dept Med Chem, Mansoura 35516, EgyptMol Imaging Innovat Inst MI3, Dept Radiol, Weill Cornell Med, New York, NY 10065 USA
Abdel-Rahman, Somaya A.
Zhang, Longfei
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Mol Imaging Innovat Inst MI3, Dept Radiol, Weill Cornell Med, New York, NY 10065 USAMol Imaging Innovat Inst MI3, Dept Radiol, Weill Cornell Med, New York, NY 10065 USA
Zhang, Longfei
Gabr, Moustafa T.
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Mol Imaging Innovat Inst MI3, Dept Radiol, Weill Cornell Med, New York, NY 10065 USAMol Imaging Innovat Inst MI3, Dept Radiol, Weill Cornell Med, New York, NY 10065 USA
机构:
Univ Turku, Fac Technol, Dept Life Technol, Biotechnol, Turku 20520, FinlandUniv Turku, Fac Technol, Dept Life Technol, Biotechnol, Turku 20520, Finland
Akter, Sultana
Lamminmaki, Urpo
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Univ Turku, Fac Technol, Dept Life Technol, Biotechnol, Turku 20520, FinlandUniv Turku, Fac Technol, Dept Life Technol, Biotechnol, Turku 20520, Finland