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

Abstract

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

Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma

“…Stock solutions were stored at − 80°C in 2.0 mL polypropylene tubes and working solutions were stored at − 20°C in glass tubes (0.5 mL). AXI and DAB were stored in amber-colored tubes (2.0 mL) due to their light sensitivity [38,39].…”

Targeted Cancer Therapy Using Compounds Activated by Light

“…While looking at the photocaged kinase inhibitors, it is also worth noticing that several kinase inhibitors intrinsically possess interesting photochemical properties. Phototoxicity was reported for vemurafenib [37], while dabrafenib can be photodegraded to a novel fluorescent BRAF V600E inhibitor [38].…”

Light-controlled inhibition of BRAFV600E kinase

“…However, Dabrafenib itself is already photochemically unstable. Upon UV light irradiation, a side-product is irreversibly formed, which is biologically less active [42]. This process might compete with photoisomerization, which makes Dabrafenib unsuitable as a starting point for a photoswitchable inhibitor.…”