Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

Boris Pinchuk; Thorsten von Drathen; Viktoria Opel; Christian Peifer

doi:10.1021/acsmedchemlett.6b00340

Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAF^V600E Inhibitor

ACS Med Chem Lett. 2016 Sep 20;7(10):962-966. doi: 10.1021/acsmedchemlett.6b00340. eCollection 2016 Oct 13.

Authors

Boris Pinchuk¹, Thorsten von Drathen¹, Viktoria Opel¹, Christian Peifer¹

Affiliation

¹ Institute of Pharmacy, University of Kiel , Gutenbergstr. 76, D-24118 Kiel, Germany.

Abstract

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.

Keywords: BRAFV600E; Dabrafenib; fluorescent probe; kinase inhibitor; photoinduced conversion.