MassIVE MSV000099766

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A dihydrouracil containing CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degraders

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Description

Immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide are clinically approved for the treatment of multiple myeloma. Although efficacious, IMiDs have been linked with adverse events associated with haematotoxicity, through the degradation of the so-called neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). Recently, IMiD substructures have been incorporated within proteolysis targeting chimeras (PROTACs) due to their ability to engage the E3 ligase CRBN and affect the degradation of a protein of interest (POI). By doing so, IMiD-based heterobifunctional degraders potentially carry safety liabilities. Herein, we disclose the profiling of several published PROTACs and demonstrate that some of them can degrade IMiD-associated neosubstrates such as Ikaros and Aiolos in addition to the targeted POI. To assess the biological consequence of degrading Ikaros, we developed in vitro assays employing hematopoietic stem and progenitor cells and a CRBN knock-in transgenic model. These assays, in conjunction with in vitro evaluation of neosubstrates degradation, establish a robust safety cascade profiling for CRBN-recruiting molecules. In parallel, a novel CRBN ligand, that can mitigate the IMiD-associated safety liabilities when incorporated into PROTACs, has been identified. This new chemical equity for CRBN, alongside the safety cascade for evaluation of PROTACs, represents a route to the preclinical development of safer PROTACs. This is of key importance as this modality matures and as clinical trials venture beyond focusing on oncological indications and delve into chronic diseases. [doi:10.25345/C53J39D82] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: CRBN ; PROTACs ; Proteomics ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Ghaith Hamza, AstraZeneca, USA
Submitting User: pravs3683
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