A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader - PubMed
5 hours ago
- #IMiDs
- #PROTACs
- #CRBN ligand
- Immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide are effective in treating multiple myeloma (MM) but pose hematotoxicity risks by degrading neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3).
- When IMiD scaffolds are integrated into proteolysis targeting chimeras (PROTACs), they can inadvertently degrade neosubstrates alongside the intended protein of interest (POI), raising safety concerns.
- The study profiles existing PROTACs and reveals instances of undesired degradation of IMiD-associated neosubstrates.
- In vitro hematopoietic assays were developed to scrutinize IMiD effects, revealing mechanistic insights on cell differentiation rewiring towards megakaryocytes and activation of the interferon response, phenocopied by an Ikaros knock-out model.
- A CRBN ligand was identified that mitigates these safety liabilities and can be effectively incorporated into PROTACs.
- This advancement provides a promising path toward safer preclinical development of PROTACs, especially for chronic disease treatments beyond oncology.