Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor
Abstract Background Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficul...
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BioMed Central
2017-05-01
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| Series: | BMC Biochemistry |
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| Online Access: | http://link.springer.com/article/10.1186/s12858-017-0083-3 |
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doaj-art-37638285f4b0452eac8bb41418b07c3a2018-08-15T23:11:47ZengBioMed CentralBMC Biochemistry1471-20912017-05-0118111510.1186/s12858-017-0083-3Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitorRobert D. Bongard0Michael Lepley1Khushabu Thakur2Marat R. Talipov3Jaladhi Nayak4Rachel A. Jones Lipinski5Chris Bohl6Noreena Sweeney7Ramani Ramchandran8Rajendra Rathore9Daniel S. Sem10Center for Structure-based Drug Design and Development, Department of Pharmaceutical Sciences, Concordia University of WisconsinDepartment of Pediatrics, Division of Neonatology, Department of Obstetrics and Gynecology, Children’s Research Institute (CRI) Developmental Vascular Biology Program, Translational and Biomedical Research CenterDepartment of Chemistry, Marquette UniversityDepartment of Chemistry, Marquette UniversityDepartment of Pediatrics, Division of Neonatology, Department of Obstetrics and Gynecology, Children’s Research Institute (CRI) Developmental Vascular Biology Program, Translational and Biomedical Research CenterDepartment of Pediatrics, Division of Neonatology, Department of Obstetrics and Gynecology, Children’s Research Institute (CRI) Developmental Vascular Biology Program, Translational and Biomedical Research CenterCenter for Structure-based Drug Design and Development, Department of Pharmaceutical Sciences, Concordia University of WisconsinCenter for Structure-based Drug Design and Development, Department of Pharmaceutical Sciences, Concordia University of WisconsinDepartment of Pediatrics, Division of Neonatology, Department of Obstetrics and Gynecology, Children’s Research Institute (CRI) Developmental Vascular Biology Program, Translational and Biomedical Research CenterDepartment of Chemistry, Marquette UniversityCenter for Structure-based Drug Design and Development, Department of Pharmaceutical Sciences, Concordia University of WisconsinAbstract Background Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Results Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. Conclusion We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.http://link.springer.com/article/10.1186/s12858-017-0083-3DUSP5pERKPTP1BAzoDyesEnzyme kinetics |
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Open Access Journals |
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Directory of Open Access Journals |
| language |
English |
| format |
Article |
| author |
Robert D. Bongard Michael Lepley Khushabu Thakur Marat R. Talipov Jaladhi Nayak Rachel A. Jones Lipinski Chris Bohl Noreena Sweeney Ramani Ramchandran Rajendra Rathore Daniel S. Sem |
| spellingShingle |
Robert D. Bongard Michael Lepley Khushabu Thakur Marat R. Talipov Jaladhi Nayak Rachel A. Jones Lipinski Chris Bohl Noreena Sweeney Ramani Ramchandran Rajendra Rathore Daniel S. Sem Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor BMC Biochemistry DUSP5 pERK PTP1B Azo Dyes Enzyme kinetics |
| author_facet |
Robert D. Bongard Michael Lepley Khushabu Thakur Marat R. Talipov Jaladhi Nayak Rachel A. Jones Lipinski Chris Bohl Noreena Sweeney Ramani Ramchandran Rajendra Rathore Daniel S. Sem |
| author_sort |
Robert D. Bongard |
| title |
Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor |
| title_short |
Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor |
| title_full |
Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor |
| title_fullStr |
Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor |
| title_full_unstemmed |
Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor |
| title_sort |
serendipitous discovery of light-induced (in situ) formation of an azo-bridged dimeric sulfonated naphthol as a potent ptp1b inhibitor |
| publisher |
BioMed Central |
| series |
BMC Biochemistry |
| issn |
1471-2091 |
| publishDate |
2017-05-01 |
| description |
Abstract Background Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Results Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. Conclusion We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds. |
| topic |
DUSP5 pERK PTP1B Azo Dyes Enzyme kinetics |
| url |
http://link.springer.com/article/10.1186/s12858-017-0083-3 |
| _version_ |
1612701540581113856 |