AI Article Synopsis
- Glutarimides like thalidomide, pomalidomide, and lenalidomide are key ligands for recruiting the E3 ubiquitin ligase cereblon (CRBN) in the creation of proteolysis-targeting chimeras (PROTACs).
- The rapid racemization of glutarimides results in a mixture where the inactive enantiomer complicates drug development, as the active form is preferred for binding to CRBN.
- A new class of ligands, substituted achiral phenyl dihydrouracil (PDHU), shows promising binding affinity to CRBN and greater stability, enabling the development of effective BRD4 degraders.
Article Abstract
Glutarimides such as thalidomide, pomalidomide, and lenalidomide are the most frequently used ligands to recruit E3 ubiquitin ligase cereblon (CRBN) for the development of proteolysis-targeting chimeras (PROTACs). Due to the rapid and spontaneous racemization of glutarimides, most CRBN-recruiting PROTACs are synthesized as a mixture of racemates or diastereomers. Since the ()-enantiomer is primarily responsible for binding to CRBN, the existence of the largely inactive ()-enantiomer complicates the drug development process. Herein, we report that substituted achiral phenyl dihydrouracil (PDHU) can be used as a novel class of CRBN ligands for the development of PROTACs. Although the parent PDHU has a minimal binding affinity to CRBN, we found that some substituted PDHUs had a comparable binding affinity to lenalidomide. Structural modeling provided a further understanding of the molecular interactions between PDHU ligands and CRBN. PDHUs also have greater stability than lenalidomide. Finally, potent BRD4 degraders were developed by employing trisubstituted PDHUs.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10398712 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.2c01941 | DOI Listing |
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Article Synopsis
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- The rapid racemization of glutarimides results in a mixture where the inactive enantiomer complicates drug development, as the active form is preferred for binding to CRBN.
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