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Controlling the covalent reactivity of a kinase inhibitor with light

DOI: 10.1002/anie.202103767 DOI Help

Authors: Martin Reynders (New York University) , Apirat Chaikuad (Goethe-Universitat Frankfurt am Main) , Benedict-Tilman Berger (Goethe-Universitat Frankfurt am Main) , Katharina Bauer (Eberhard Karls Universitat Tubingen) , Pierre Koch (Eberhard Karls Universitat Tubingen) , Stefan Laufer (Eberhard Karls Universitat Tubingen) , Stefan Knapp (Goethe-Universitat Frankfurt am Main) , Dirk Trauner (New York University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: June 2021

Abstract: Covalent kinase inhibitors account for some of the most successful drugs that have recently entered the clinic and many others are in preclinical development. A common strategy is to target cysteines in the vicinity of the ATP binding site using an acrylamide electrophile. To increase the tissue selectivity of kinase inhibitors, it could be advantageous to control the reactivity of these electrophiles with light. Here, we introduce covalent inhibitors of the kinase JNK3 that function as photoswitchable affinity labels (PALs). Our lead compounds contain a diazocine photoswitch, are poor non-covalent inhibitors in the dark, and becomes effective covalent inhibitors after irradiation with visible light. Our proposed mode of action is supported by X-ray structures that explain why these compounds are unreactive in the dark and undergo proximity-based covalent attachment following exposure to light.

Journal Keywords: covalent inhibito;r photopharmacology; photoswitch; photoswitchable affinity label; JNK3

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Other Facilities: 14.2 at BESSY

Added On: 08/06/2021 09:27

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)