Crystal structure of p38alpha in complex with a reduced photoswitchable 2-Azothiazol-based Inhibitor (compound 31)

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 become 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.

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Controlling the Covalent Reactivity of a Kinase Inhibitor with Light

Reynders

Chaikuad

Berger

et al. 2021

Angew Chem Int Ed

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Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor

et al. 2022

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Eg5 is a kinesin motor protein that is responsible for bipolar spindle formation and plays a crucial role during mitosis. Loss of Eg5 function leads to the formation of monopolar spindles, followed by mitotic arrest, and subsequent cell death. Several cell‐permeable small molecules have been reported to inhibit Eg5 and some have been evaluated as anticancer agents. We now describe the design, synthesis, and biological evaluation of photoswitchable variants with five different pharmacophores. Our lead compound Azo‐EMD is a cell permeable azobenzene that inhibits Eg5 more potently in its light‐induced cis form. This activity decreased the velocity of Eg5 in single‐molecule assays, promoted formation of monopolar spindles, and led to mitotic arrest in a light dependent way.

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Light‐Controlled Destruction and Assembly: Switching between Two Differently Composed Cage‐Type Complexes

et al. 2022

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We report on two regioisomeric, diazocine ligands 1 and 2 that can both be photoswitched between the E‐ and Z‐configurations with violet and green light. The self‐assembly of the four species (1‐Z, 1‐E, 2‐Z, 2‐E) with CoII ions was investigated upon changing the coordination vectors as a function of the ligand configuration (E vs Z) and regioisomer (1 vs 2). With 1‐Z, Co2(1‐Z)3 was self‐assembled, while a mixture of ill‐defined species (oligomers) was observed with 2‐Z. Upon photoswitching with 385 nm to the E configurations, the opposite was observed with 1‐E forming oligomers and 2‐E forming Co2(2‐E)3. Light‐controlled dis/assembly was demonstrated in a ligand competition experiment with sub‐stoichiometric amounts of CoII ions; alternating irradiation with violet and green light resulted in the reversible transformation between Co2(1‐Z)3 and Co2(2‐E)3 over multiple cycles without significant fatigue by photoswitching.

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Crystal structure of p38alpha in complex with a reduced photoswitchable 2-Azothiazol-based Inhibitor (compound 31)

Cited by 13 publications

References 52 publications

Controlling the Covalent Reactivity of a Kinase Inhibitor with Light

Controlling the Covalent Reactivity of a Kinase Inhibitor with Light

Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor

Light‐Controlled Destruction and Assembly: Switching between Two Differently Composed Cage‐Type Complexes

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