Novel Mechanism for an Old Drug: Phenazopyridine is a Kinase Inhibitor Affecting Autophagy and Cellular Differentiation

Article Article scientifique Article Novel Mechanism for an Old Drug: Phenazopyridine is a Kinase Inhibitor Affecting Autophagy and Cellular Differentiation eng 2021-08-04 2021 author Preynat-Seauve Olivier Laboratory of Therapy and Stem Cells, Department of Diagnostics, Geneva University Hospitals, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 561776 Département de médecine (DEMED) author Nguyen Evelyne Bao-Vi Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 834893 author Westermaier Yvonne Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva, Switzerland. 629529 author Heritier Margaux Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva, Switzerland. 835570 Section des sciences pharmaceutiques (FARMA) author Tardy Sébastien Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva, Switzerland. 784523 Section des sciences pharmaceutiques (FARMA) author Cambet Yves Alexandre READS Unit, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 33476 Services communs de la faculté de médecine (SCMU) author Feyeux Maxime Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 755543 author Caillon Aurélie Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 126300 Département de pathologie et immunologie (PATIM) author Scapozza Leonardo Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva, Switzerland. 600318 Section des sciences pharmaceutiques (FARMA) author Krause Karl-Heinz Laboratory of Therapy and Stem Cells, Department of Diagnostics, Geneva University Hospitals, Geneva, Switzerland.,Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 23022 Département de pathologie et immunologie (PATIM) 664608 10.3389/fphar.2021.664608 34421588 1663-9812 PMC8371461 Phenazopyridine is a widely used drug against urinary tract pain. The compound has also been shown to enhance neural differentiation of pluripotent stem cells. However, its mechanism of action is not understood. Based on its chemical structure, we hypothesized that phenazopyridine could be a kinase inhibitor. Phenazopyridine was investigated in the following experimental systems: 1) activity of kinases in pluripotent stem cells; 2) binding to recombinant kinases, and 3) functional impact on pluripotent stem cells. Upon addition to pluripotent stem cells, phenazopyridine induced changes in kinase activities, particularly involving Mitogen-Activated Protein Kinases, Cyclin-Dependent Kinases, and AKT pathway kinases. To identify the primary targets of phenazopyridine, we screened its interactions with 401 human kinases. Dose-inhibition curves showed that three of these kinases interacted with phenazopyridine with sub-micromolar binding affinities: cyclin-G-associated kinase, and the two phosphatidylinositol kinases PI4KB and PIP4K2C, the latter being known for participating in pain induction. Docking revealed that phenazopyridine forms strong H-bonds with the hinge region of the ATP-binding pocket of these kinases. As previous studies suggested increased autophagy upon inhibition of the phosphatidyl-inositol/AKT pathway, we also investigated the impact of phenazopyridine on this pathway and found an upregulation. In conclusion, our study demonstrates for the first time that phenazopyridine is a kinase inhibitor, impacting notably phosphatidylinositol kinases involved in nociception. Autophagy Differentiation Kinase Phenazopyridine Phosphatidylinositol kinase Dewey 615 Dewey 616.07 Dewey 616 137 Département de pathologie et immunologie 21F 31 Section des sciences pharmaceutiques 17 56 Département de médecine 221 false 38 Radicaux libres et cellules souches embryonnaires 60 950 Génomique et métagénomique des produits sanguins labiles 956 880 Biochimie pharmaceutique Frontiers in pharmacology 12 19ab7c79-ac83-4983-8693-d0e989b158cb Article (Published version) Public Article-scientifique-from-europePmc.pdf 1927441 application/pdf CC BY 46ea33a03a8a1a5c5e5b128ed825c80ce75252a63a712fbe98cb0557c1dbcb0c b17f7bb3-ece4-4380-99a0-642773490c23 Appendix Public Table1.XLSX 22485 application/octet-stream b527074d35399abfc5246986ccba311e2677680e4cb2e02240e0457b21e0c44f 76a00cad-36b9-4d4b-b8cc-469a229d8543 Appendix Public Table2.XLSX 152530 application/octet-stream 9f4d98905f0efc46eb570e47edc5d8b14cfd63c2fc0f1a7d831939c2be30adc9 11ac5d13-1003-409e-b40e-e31fcf751b8d Appendix Public Table3.XLSX 66398 application/octet-stream 1733c8b7b06dabff808eb7fe53181516ef6b3cac0d721770b35b931ec4a2daf6 7e92449a-d66c-4afa-9ea6-1ff475193fd4 Appendix Public Table4.XLSX 16991 application/octet-stream 7d4562a7b113ba0ac5adac5e41a09862274ee4c7dd75fce18f8c0a2e00d04e62 809584be-26b5-4282-9b02-2325050d95db Appendix Public Image1.JPEG 116737 image/jpeg 267168a5c6691a65dd0d3722cd38dd316b6e4dedc0d0452140d025fb178ecc14 1c774ccd-a8f4-4365-8e15-ac9627baac1a Appendix Public Image2.JPEG 94542 image/jpeg 1cc0b27ebc413dd71bb16c9c9c5e3b9483b40596503493d98451110ca111702c 709a914d-1041-47ae-97a1-6fe1e613cc0c Appendix Public Image3.JPEG 151938 image/jpeg 7c65537a7799cd721423a31d957e1e787a323ee2fab3135a236c570eb3399a9e openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département de médecine

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Novel Mechanism for an Old Drug: Phenazopyridine is a Kinase Inhibitor Affecting Autophagy and Cellular Differentiation	Frontiers in pharmacology			2021	152	256

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Nguyen, Evelyne Bao-Vi