title: Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600EInhibitor.
abstract: Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAFV600Emutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAFV600E/Kmutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo2. This novel compound could be isolated and biologically characterizedin vitro. Both enzymatic and cellular assays proved that2is still a potent BRAFV600Einhibitor. The intracellular formation of2from dabrafenib upon ultraviolet irradiation is shown. The herein presented findings should be taken in account when handling dabrafenib both in preclinical research and in clinical applications.
authors: Institute of Pharmacy, University of Kiel , Gutenbergstr. 76, D-24118 Kiel, Germany.
authors: Boris
authors: B
authors: Pinchuk
authors: Institute of Pharmacy, University of Kiel , Gutenbergstr. 76, D-24118 Kiel, Germany.
authors: Thorsten
authors: T
authors: von Drathen
authors: Institute of Pharmacy, University of Kiel , Gutenbergstr. 76, D-24118 Kiel, Germany.
authors: Viktoria
authors: V
authors: Opel
authors: Institute of Pharmacy, University of Kiel , Gutenbergstr. 76, D-24118 Kiel, Germany.
authors: Christian
authors: C
authors: Peifer
keywords: BRAFV600E; Dabrafenib; fluorescent probe; kinase inhibitor; photoinduced conversion