title: Photoactivatable Prodrugs of Antimelanoma Agent Vemurafenib.
abstract: In this study, we report on novel photoactivatable caged prodrugs of vemurafenib. This kinase inhibitor was the first approved drug for the personalized treatment of BRAF-mutated melanoma and showed impressive results in clinical studies. However, the occurrence of severe side effects and drug resistance illustrates the urgent need for innovative therapeutic approaches. To conquer these limitations, we implemented photoremovable protecting groups into vemurafenib. In general, this caging concept provides spatial and temporal control over the activation of molecules triggered by ultraviolet light. Thus, higher inhibitor concentrations in tumor tissues might be reached with less systemic effects. Our study describes the first development of caged vemurafenib prodrugs useful as pharmacological tools. We investigated their photochemical characteristics and photoactivation. In vitro evaluation proved the intended loss-of-function and the light-dependent recovery of efficacy in kinase and cellular assays. The reported vemurafenib photo prodrugs represent a powerful biological tool for novel pharmacological approaches in cancer research.
authors.affiliation: Pharmaceutical Chemistry, Christian Albrechts University , Gutenbergstraße 76, 24118 Kiel, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Horbert
authors.affiliation: Pharmaceutical Chemistry, Christian Albrechts University , Gutenbergstraße 76, 24118 Kiel, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Pinchuk
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
authors.forename: Dario
authors.initials: D
authors.lastname: Alessi
authors.affiliation: Pharmaceutical Chemistry, Christian Albrechts University , Gutenbergstraße 76, 24118 Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peifer
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008958:Models, Molecular; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D017319:Photosensitizing Agents; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf