Photoinduced Conversion of Antimelanoma Agent Dabrafenibto a Novel Fluorescent BRAFV600E Inhibitor

摘要

Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAF^V600E mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAF^V600E/K mutant 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_photo >2. This novel compound could be isolated and biologically characterized in vitro. Both enzymatic and cellular assays proved that >2 is still a potent BRAF^V600E inhibitor. The intracellular formation of >2 from 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.