One-pot domino synthesis of 1H-isochromene and pyran carbonitrile from pyrazole aldehyde derivatives as potential anti-diabetic and antioxidant targets

Journal of Molecular Structure, Год журнала: 2024, Номер 1311, С. 138308 - 138308

Опубликована: Апрель 10, 2024

Язык: Английский

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Identification of Suitable Target/E3 Ligase Pairs for PROTAC Development using a Rapamycin-induced Proximity Assay (RiPA)

eLife, Год журнала: 2024, Номер 13

Опубликована: Июль 26, 2024

The development of proteolysis targeting chimeras (PROTACs), which induce the degradation target proteins by bringing them into proximity with cellular E3 ubiquitin ligases, has revolutionized drug development. While human genome encodes more than 600 different current PROTACs use only a handful them, drastically limiting their full potential. Furthermore, many PROTAC campaigns fail because selected ligase candidates are unable to particular interest. As and ligands for novel ligases discovered, chemical effort identify best given is exploding. Therefore, genetic system degradation-causing suitable target/E3 pairs urgently needed. Here, we used well-established dimerization FKBP12 protein FRB domain rapamycin bring WDR5 candidate ligases. Strikingly, this rapamycin-induced assay (RiPA) revealed that VHL, but not Cereblon, able - finding previously made PROTACs, demonstrating its predictive power. By optimizing steric arrangement all components fusing minimal luciferase, RiPA can ideal any interest in living cells, significantly reducing focusing early stages

Язык: Английский

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Identification of suitable target/E3 ligase pairs for PROTAC development using a rapamycin-induced proximity assay (RiPA)

eLife, Год журнала: 2024, Номер 13

Опубликована: Дек. 6, 2024

The development of proteolysis targeting chimeras (PROTACs), which induce the degradation target proteins by bringing them into proximity with cellular E3 ubiquitin ligases, has revolutionized drug development. While human genome encodes more than 600 different current PROTACs use only a handful them, drastically limiting their full potential. Furthermore, many PROTAC campaigns fail because selected ligase candidates are unable to particular interest. As and ligands for novel ligases discovered, chemical effort identify best given is exploding. Therefore, genetic system degradation-causing suitable target/E3 pairs urgently needed. Here, we used well-established dimerization FKBP12 protein FRB domain rapamycin bring WDR5 candidate ligases. Strikingly, this rapamycin-induced assay (RiPA) revealed that VHL, but not Cereblon, able - finding previously made PROTACs, demonstrating its predictive power. By optimizing steric arrangement all components fusing minimal luciferase, RiPA can ideal any interest in living cells, significantly reducing focusing early stages

Язык: Английский

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Rapid PROTAC discovery platform: nanomole scale array synthesis and direct screening of reaction mixtures to facilitate the expedited discovery and follow-up of PROTAC hits.

Опубликована: Июль 18, 2023

Precise linker length, shape and attachment point are all integral components to designing efficacious PROTACs. Due the increased synthetic complexity of these heterobifunctional degraders difficulty computational modelling aid PROTAC design, exploration structure-activity-relationship (SAR) remains mostly empirical, which requires a significant time resource investment. To facilitate rapid hit finding we developed capabilities for parallel synthesis purification by harnessing an array pre-formed E3-ligand intermediates. In next iteration this approach, rapid, nanomole-scale methodology using amide coupling that enables direct screening non-purified reaction mixtures in cell-based degradation assays, as well logD EPSA measurements. This approach greatly expands accelerates SAR (5 days instead several weeks) while nanomole amounts reagents. Lastly, it avoids laborious solvent-demanding mixtures, thus making economical more sustainable finding.

Язык: Английский

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A review of volumetric titration as an efficient method for the quantification of ions and compounds in lithium-ion battery components

Chemical Papers, Год журнала: 2023, Номер 77(12), С. 7395 - 7408

Опубликована: Сен. 21, 2023

Язык: Английский

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