Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A

Miyazaki, Youichi; Kikuchi, Masaki; Umezawa, Koji; Descamps, Aurélie; Nakamura, Daichi; Furuie, Gaku; Sumida, Tomoe; Saito, Kanako; Kimura, Ninako; Niwa, Takashi; Sumida, Yuto; Umehara, Takashi; Hosoya, Takamitsu; Kii, Isao

doi:10.1016/j.ejmech.2021.113948

Cited by 7 publications

(2 citation statements)

References 76 publications

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“…FINDY (41). 120,121 FINDY, like a recently described analogue dp-FINDY, 122 is an intermediate-selective inhibitor of DYRK1A (but not DYRK1B nor DYRK2) acting through the inhibition of the intramolecular Ser97 autophosphorylation. FINDY does not fit into the ATP-binding pocket of mature DYRK1A and does not inhibit the fully activated kinase.…”

Section: ■ Resultsmentioning

confidence: 99%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

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Section: ■ Resultsmentioning

confidence: 99%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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“…32 This example nicely illustrates the utility of this methodology with respect to functional group tolerance. Related DYRK1A inhibitor 33 analogues 4c 1 −4e 1 were also synthesized in good yields. Autotaxin inhibitor 34 analogue 4f 1 , bearing a benzylic phosphonate, reacted efficiently.…”

Section: Resultsmentioning

confidence: 99%

One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development

Rivas,

Debnath,

Giri

et al. 2023

J. Am. Chem. Soc.

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We report the first one-pot formal alkene carboradiofluorination reaction employing easily accessible alkenes as both prosthetic group precursors and coupling partners. The methodology features rapid sequential Markovnikov-selective iodofluorination and photoinduced Pd(0/I/II)-catalyzed alkyl Heck reaction as a mild and robust fluorine-18 ( 18 F) radiochemical approach for positron emission tomography (PET) imaging probe development. A new class of prosthetic groups for PET imaging probe synthesis was isolated as iodofluorinated intermediates in moderate to excellent yields. The one-pot formal alkenylfluorination reaction was carried out to produce over 30 analogues of a wide range of bioactive molecules. Further application of the Pd(0/ I/II) manifold in PET probe development was illustrated by the direct carbo(radio)fluorination of electron-rich alkenes. The methods were successfully translated to radiolabel a broad scope of medicinally relevant small molecules in generally good radiochemical conversion. The protocol was further optimized to accommodate no-carrier-added conditions with similar efficiency for future (pre)clinical translation. Moreover, the radiosynthesis of prosthetic groups was automated in a radiochemistry module to facilitate its practical use in multistep radiochemical reactions.

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Dual Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors: The Quest for a Disease-Modifying Treatment for Alzheimer’s Disease

Sukanya,

Prajapati,

Patil

et al. 2023

Deciphering Drug Targets for Alzheimer’s Disease

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Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A

Cited by 7 publications

References 76 publications

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development

Dual Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors: The Quest for a Disease-Modifying Treatment for Alzheimer’s Disease

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