Light-controlled inhibition of BRAFV600E kinase

Mark W H Hoorens, Maria E Ourailidou, Theo Rodat, Petra E van der Wouden, Piermichele Kobauri, Malte Kriegs, Christian Peifer, Ben L Feringa, Frank J Dekker, Wiktor Szymanski*

*Bijbehorende auteur voor dit werk

Onderzoeksoutput: ArticleAcademicpeer review

27 Citaten (Scopus)
90 Downloads (Pure)


Metastatic melanoma is amongst the most difficult types of cancer to treat, with current therapies mainly relying on the inhibition of the BRAFV600E mutant kinase. However, systemic inhibition of BRAF by small molecule drugs in cancer patients results - paradoxically - in increased wild-type BRAF activity in healthy tissue, causing side-effects and even the formation of new tumors. Here we show the development of BRAFV600E kinase inhibitors of which the activity can be switched on and off reversibly with light, offering the possibility to overcome problems of systemic drug activity by selectively activating the drug at the desired site of action. Based on a known inhibitor, eight photoswitchable effectors containing an azobenzene photoswitch were designed, synthesized and evaluated. The most promising inhibitor showed an approximately 10-fold increase in activity upon light-activation. This research offers inspiration for the development of therapies for metastatic melanoma in which tumor tissue is treated with an active BRAFV600E inhibitor with high spatial and temporal resolution, thus limiting the damage to other tissues.

Originele taal-2English
Pagina's (van-tot)133-146
Aantal pagina's14
TijdschriftEuropean Journal of Medicinal Chemistry
StatusPublished - 1-okt.-2019

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