The Experts below are selected from a list of 7452 Experts worldwide ranked by ideXlab platform
David K Stammers - One of the best experts on this subject based on the ideXlab platform.
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structural basis for non competitive product inhibition in human thymidine phosphorylase implications for drug design
Biochemical Journal, 2006Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Jan Balzarini, Mariajesus Perezperez, David K StammersAbstract:HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by Ribose Phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before Ribose Phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
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Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design
Biochemical Journal, 2006Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Maris-jésus Pérez-pérez, Jan Balzarini, David K StammersAbstract:Human Thymidine Phosphorylase (HTP), also known as Platelet-derived endothelial cell growth factor (PD-ECGF) or Gliostatin has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis, therefore is a prime target for drug design including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by Ribose-Phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears able to reassociate with HTP after its initial ordered release before Ribose-Phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase (PYNP) and it defines a sub site that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active site cleft and appears to stabilise the dimer interface and the closed conformation by hydrogen bonding. This work will assist in the design of HTP inhibitors which could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
David R. Langley - One of the best experts on this subject based on the ideXlab platform.
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5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Harold Mastalerz, Ming Chang, Ping Chen, Brian E. Fink, Ashvinikumar V. Gavai, Wen-ching Han, Johnson Walter Lewis, David R. Langley, Francis Y. Lee, Kenneth J. LeavittAbstract:Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the Ribose-Phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
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Novel C-5 aminomethyl pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Harold Mastalerz, Ming Chang, Ashvinikumar V. Gavai, Johnson Walter Lewis, David R. Langley, Francis Y. Lee, Punit Marathe, Arvind Mathur, Simone Oppenheimer, James G. TarrantAbstract:Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the Ribose-Phosphate portion of the ATP binding pocket.
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New C-5 substituted pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Harold Mastalerz, Ming Chang, Ping Chen, Pierre Dextraze, Brian E. Fink, Ashvinikumar V. Gavai, Bindu Goyal, Wen-ching Han, Johnson Walter Lewis, David R. LangleyAbstract:Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the Ribose Phosphate portion of the ATP binding pocket.
Harold Mastalerz - One of the best experts on this subject based on the ideXlab platform.
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5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Harold Mastalerz, Ming Chang, Ping Chen, Brian E. Fink, Ashvinikumar V. Gavai, Wen-ching Han, Johnson Walter Lewis, David R. Langley, Francis Y. Lee, Kenneth J. LeavittAbstract:Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the Ribose-Phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
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Novel C-5 aminomethyl pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Harold Mastalerz, Ming Chang, Ashvinikumar V. Gavai, Johnson Walter Lewis, David R. Langley, Francis Y. Lee, Punit Marathe, Arvind Mathur, Simone Oppenheimer, James G. TarrantAbstract:Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the Ribose-Phosphate portion of the ATP binding pocket.
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New C-5 substituted pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Harold Mastalerz, Ming Chang, Ping Chen, Pierre Dextraze, Brian E. Fink, Ashvinikumar V. Gavai, Bindu Goyal, Wen-ching Han, Johnson Walter Lewis, David R. LangleyAbstract:Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the Ribose Phosphate portion of the ATP binding pocket.
Sandra Liekens - One of the best experts on this subject based on the ideXlab platform.
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structural basis for non competitive product inhibition in human thymidine phosphorylase implications for drug design
Biochemical Journal, 2006Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Jan Balzarini, Mariajesus Perezperez, David K StammersAbstract:HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by Ribose Phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before Ribose Phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
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Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design
Biochemical Journal, 2006Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Maris-jésus Pérez-pérez, Jan Balzarini, David K StammersAbstract:Human Thymidine Phosphorylase (HTP), also known as Platelet-derived endothelial cell growth factor (PD-ECGF) or Gliostatin has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis, therefore is a prime target for drug design including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by Ribose-Phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears able to reassociate with HTP after its initial ordered release before Ribose-Phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase (PYNP) and it defines a sub site that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active site cleft and appears to stabilise the dimer interface and the closed conformation by hydrogen bonding. This work will assist in the design of HTP inhibitors which could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
Annelies Bronckaers - One of the best experts on this subject based on the ideXlab platform.
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structural basis for non competitive product inhibition in human thymidine phosphorylase implications for drug design
Biochemical Journal, 2006Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Jan Balzarini, Mariajesus Perezperez, David K StammersAbstract:HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by Ribose Phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before Ribose Phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
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Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design
Biochemical Journal, 2006Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Maris-jésus Pérez-pérez, Jan Balzarini, David K StammersAbstract:Human Thymidine Phosphorylase (HTP), also known as Platelet-derived endothelial cell growth factor (PD-ECGF) or Gliostatin has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis, therefore is a prime target for drug design including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by Ribose-Phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears able to reassociate with HTP after its initial ordered release before Ribose-Phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase (PYNP) and it defines a sub site that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active site cleft and appears to stabilise the dimer interface and the closed conformation by hydrogen bonding. This work will assist in the design of HTP inhibitors which could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
