The Experts below are selected from a list of 144 Experts worldwide ranked by ideXlab platform
Youla S Tsantrizos - One of the best experts on this subject based on the ideXlab platform.
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thienopyrimidine bisphosphonate thpbp inhibitors of the human farnesyl pyrophosphate synthase optimization and characterization of the mode of inhibition
Journal of Medicinal Chemistry, 2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
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Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition
2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics
Chun Yuen Leung - One of the best experts on this subject based on the ideXlab platform.
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thienopyrimidine bisphosphonate thpbp inhibitors of the human farnesyl pyrophosphate synthase optimization and characterization of the mode of inhibition
Journal of Medicinal Chemistry, 2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
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Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition
2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics
Thomas J Meyer - One of the best experts on this subject based on the ideXlab platform.
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sensitized photodecomposition of organic bisphosphonates by singlet oxygen
Journal of the American Chemical Society, 2012Co-Authors: Kenneth Hanson, Dennis L Ashford, Javier J Concepcion, Robert A Binstead, Sohrab Habibi, Christopher R K Glasson, Joseph L Templeton, Thomas J MeyerAbstract:During efforts to stabilize metal oxide bound chromophores for photoelectrochemical applications, a novel photochemical reaction has been discovered. In the reaction, the bisphosphonate functional groups −C(PO3H2)2(OH) in the metal complex [Ru(bpy)2(4,4′-(C(OH)(PO3H2)2bpy)]2+ are converted into −COOH and H3PO4. The reaction occurs by sensitized formation of 1O2 by the lowest metal-to-ligand charge transfer excited state(s) of [Ru(bpy)2(4,4′-(C(PO3H2)2(OH))2(bpy))]2+* followed by 1O2 oxidation of the bisphosphonate substituent. A related reaction occurs for the bisphosphonate-based drug, Risedronic Acid, in the presence of O2, light, and a singlet oxygen sensitizer ([Ru(bpy)3]2+ or Rose Bengal).
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Sensitized Photodecomposition of Organic Bisphosphonates By Singlet Oxygen
2012Co-Authors: Kenneth Hanson, Dennis L Ashford, Javier J Concepcion, Robert A Binstead, Sohrab Habibi, Christopher R K Glasson, Joseph L Templeton, Hanlin Luo, Thomas J MeyerAbstract:During efforts to stabilize metal oxide bound chromophores for photoelectrochemical applications, a novel photochemical reaction has been discovered. In the reaction, the bisphosphonate functional groups −C(PO3H2)2(OH) in the metal complex [Ru(bpy)2(4,4′-(C(OH)(PO3H2)2bpy)]2+ are converted into −COOH and H3PO4. The reaction occurs by sensitized formation of 1O2 by the lowest metal-to-ligand charge transfer excited state(s) of [Ru(bpy)2(4,4′-(C(PO3H2)2(OH))2(bpy))]2+* followed by 1O2 oxidation of the bisphosphonate substituent. A related reaction occurs for the bisphosphonate-based drug, Risedronic Acid, in the presence of O2, light, and a singlet oxygen sensitizer ([Ru(bpy)3]2+ or Rose Bengal)
Jaeok Park - One of the best experts on this subject based on the ideXlab platform.
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thienopyrimidine bisphosphonate thpbp inhibitors of the human farnesyl pyrophosphate synthase optimization and characterization of the mode of inhibition
Journal of Medicinal Chemistry, 2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
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Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition
2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics
Joris W De Schutter - One of the best experts on this subject based on the ideXlab platform.
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thienopyrimidine bisphosphonate thpbp inhibitors of the human farnesyl pyrophosphate synthase optimization and characterization of the mode of inhibition
Journal of Medicinal Chemistry, 2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
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Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition
2013Co-Authors: Chun Yuen Leung, Jaeok Park, Joris W De Schutter, Michael Sebag, Albert M Berghuis, Youla S TsantrizosAbstract:Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug Risedronic Acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics
