Investigation of the phenyl dihydrouracil molecules as CRBN ligands for the PROTAC development

Authors

  • V. O. Stadnichenko Enamine Ltd. 78, Winston Churchill Str., Kyiv, Ukraine, 02094; Taras Shevchenko National University of Kyiv 64, Volodymyrska Str., Kyiv, Ukraine, 01601 Author
  • O. V. Yakymchuk Enamine Ltd. 78, Winston Churchill Str., Kyiv, Ukraine, 02094 Author
  • P. O. Borysko Enamine Ltd. 78, Winston Churchill Str., Kyiv, Ukraine, 02094 Author
  • G. M. Tolstanova Taras Shevchenko National University of Kyiv 64, Volodymyrska Str., Kyiv, Ukraine, 01601 Author
  • O. S. Shyshlyk Enamine Ltd. 78, Winston Churchill Str., Kyiv, Ukraine, 02094 Author
  • O. O. Grygorenko Enamine Ltd. 78, Winston Churchill Str., Kyiv, Ukraine, 02094 Author

DOI:

https://doi.org/10.7124/bc.000AF1

Keywords:

CRBN, PROTAC, phenyl dihydrouracil, pomalidomide, fluorescence polarization

Abstract

Aim. CRBN is the most widely used E3 ligase for PROTACs development due to the large variety of its glutarimide ligands, which have good drug-like properties and low molecular weight. However, because of the racemization and low stability of glutarimides, the process of drug development faces many challenges [1-2]. This work aims to study and analyze the set of more stable phenyl dihydrouracil molecules as promising binders for CRBN. These investigations will be helpful during the development of PROTACs. Conclusions. The IC50 value of tested phenyl dihydrouracil Compound 1 is similar to the well-known Cereblonglutarimide ligand pomalidomide, which indicates that phenyl dihydrouracils might be a good replacement for the Thalidomide derivatives with the potential to be used during CRBN-based PROTACs development.

References

Bekes M et al. PROTAC Targeted Protein Degraders: The Past Is Prologue. Nat. Rev. DrugDiscov. 2022; 21(3):181–200.

Wang C et al. Developments of CRBN-Based PROTACs as Potential Therapeutic Agents. Eur. J. Med. Chem. 2021; 225:113749.

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Published

2024-09-10

Issue

Vol. 40 No. 3 (2024)

Section

Chronicle and Information