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Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs |
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| Authors: | Scott Latanya M Chen Liwei Daniel Kenyon G Brooks Wesley H Guida Wayne C Lawrence Harshani R Sebti Said M Lawrence Nicholas J Wu Jie |
| Affiliation: | a Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA b High Throughput Screening and Chemistry Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA c Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA d Department of Oncologic Sciences, University of South Florida College of Medicine, Tampa, FL, USA e Department of Chemistry, University of South Florida, USA |
| Abstract: | Shp2 protein tyrosine phosphate (PTP) is a novel target for anticancer drug discovery. We identified estramustine phosphate as a Shp2 PTP inhibitor from the National Cancer Institute Approved Oncology Drug set. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triterpenoids, enoxolone, and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors. |
| Keywords: | Shp2 Protein tyrosine phosphatase Estramustine phosphate Enoxolone Celastrol Triterpenoids |
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