Controlling the Covalent Reactivity of a Kinase Inhibitor with Light

Reynders, Martin; Chaikuad, A.; Berger, Benedict‐Tilman; Koch, Pierre; Laufer, Stefan; Knapp, Stefan; Trauner, Dirk

doi:10.1002/ange.202103767

Angewandte Chemie

2021

DOI: 10.1002/ange.202103767

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Controlling the Covalent Reactivity of a Kinase Inhibitor with Light

Martin Reynders

A. Chaikuad

Benedict‐Tilman Berger

et al.

Abstract: Figure 3. In vitro characterization. Quantitative ELISA assay of differential ATF-2 phosphorylation by JNK3 for 50 min at 37 8C in the dark or with pulsed irradiation (100 ms every 5 s) and inhibitors:

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Cited by 2 publications

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References 33 publications

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“…Therefore, brain-penetrant JNK3-selective inhibitors are highly sought after as tools to investigate and as treatments for these CNS diseases . Many JNK3 inhibitors have been identified and developed − but so far none of them have been advanced to clinical trials for treating CNS diseases. The reason might be due to either inadequate ADMET properties (including brain-penetration capability) of existing JNK3 inhibitors or mechanism-based issues related to the JNK3 pathways.…”

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confidence: 99%

N-Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors

Feng

Park

Ryu

et al. 2021

ACS Med. Chem. Lett.

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An indazole/aza-indazole scaffold was developed as a novel chemotype for JNK3 inhibition. Extensive structure activity relationship (SAR) studies utilizing various in vitro and in vivo assays led to potent and highly selective JNK3 inhibitors with good oral bioavailability and high brain penetration. One lead compound, 29, was a potent and selective JNK3 inhibitor (IC 50 = 0.005 μM) that had significant inhibition (>80% at 1 μM) to only JNK3 and JNK2 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in the human liver microsome (t 1/2 = 92 min), and was orally bioavailable and brain penetrant (brain/plasma ratio: 56%). The cocrystal structure of 29 in human JNK3 at a 2.1 Å resolution showed that indazole or aza-indazole-based JNK3 inhibitors demonstrated a type I kinase inhibition/binding.

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confidence: 99%

N-Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors

Feng

Park

Ryu

et al. 2021

ACS Med. Chem. Lett.

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Visible Light‐Driven Molecular Switches and Motors: Recent Developments and Applications

Wang

Bisoyi

Zhang

et al. 2022

Chemistry A European J

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Inspired by human vision, a diverse range of light‐driven molecular switches and motors have been developed for fundamental understanding and application in material science and biology. Recently, the design and synthesis of visible light‐driven molecular switches and motors have been actively pursued. This emerging trend is partly motivated to avoid the harmful effects of ultraviolet light, which was necessary to drive the classical molecular switches and motors at least in one direction, impeding their employment in biomedical and photopharmacology applications. Moreover, visible light‐driven molecular switches and motors are demonstrated to enable benign optical materials for advanced photonic devices. Therefore, during the past several years, visible light‐driven molecular switches based on azobenzene derivatives, diarylethenes, 1,2‐dicyanodithienylethenes, hemithioindigo derivatives, iminothioindoxyls, donor‐acceptor Stenhouse adducts, and overcrowded alkene based molecular motors have been judiciously designed, synthesized, and used in the development of functional materials and systems for a wide range of applications. In this Review, we present the recent developments toward the design of visible light‐driven molecular switches and motors, with their applications in the fabrication of functional materials and systems in material science, bioscience, pharmacology, etc. The visible light‐driven molecular switches and motors realized so far undoubtedly widen the scope of these interesting compounds for technological and biological applications. We hope this Review article could provide additional impetus and inspire further research interests for future exploration of visible light‐driven advanced materials, systems, and devices.

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Controlling the Covalent Reactivity of a Kinase Inhibitor with Light

Abstract: Figure 3. In vitro characterization. Quantitative ELISA assay of differential ATF-2 phosphorylation by JNK3 for 50 min at 37 8C in the dark or with pulsed irradiation (100 ms every 5 s) and inhibitors:

Cited by 2 publications

References 33 publications

N-Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors

N-Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors

Visible Light‐Driven Molecular Switches and Motors: Recent Developments and Applications

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