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

doi:10.1016/j.ejmech.2019.06.042

Light-controlled inhibition of BRAFV600E kinase

Eur J Med Chem. 2019 Oct 1:179:133-146. doi: 10.1016/j.ejmech.2019.06.042. Epub 2019 Jun 18.

Affiliations

¹ University Medical Center Groningen, Department of Radiology, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands; Stratingh Institute for Chemistry, Faculty of Science and Engineering, University of Groningen, Nijenborgh 7, 9747 AG Groningen, Netherlands.
² Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
³ Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstr. 76, 24118 Kiel, Germany.
⁴ Stratingh Institute for Chemistry, Faculty of Science and Engineering, University of Groningen, Nijenborgh 7, 9747 AG Groningen, Netherlands.
⁵ Laboratory of Radiobiology & Experimental Radiooncology and UCCH Kinomics Core Facility, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
⁶ University Medical Center Groningen, Department of Radiology, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands; Stratingh Institute for Chemistry, Faculty of Science and Engineering, University of Groningen, Nijenborgh 7, 9747 AG Groningen, Netherlands. Electronic address: w.szymanski@umcg.nl.

PMID: 31252305
DOI: 10.1016/j.ejmech.2019.06.042

Abstract

Metastatic melanoma is amongst the most difficult types of cancer to treat, with current therapies mainly relying on the inhibition of the BRAF^V600E 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 BRAF^V600E 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 BRAF^V600E inhibitor with high spatial and temporal resolution, thus limiting the damage to other tissues.

Keywords: Azobenzene; BRAF(V600E); Metastatic melanoma; Photocontrolled inhibitor; Photopharmacology.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Binding Sites / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Light*
Melanoma / drug therapy*
Melanoma / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf