Abstract 7269: The humanized CRBN mice model facilitates PROTACs studies based on CRBN ligands

Abstract CRBN ligands, which have become increasingly popular as E3 ligase ligands, are important in designing PROTACs (Proteolysis Targeting Chimeras) and molecular glue degraders, aiding in targeted protein degradation. CRBN, part of the CRL4 E3 ubiquitin ligase complex, binds to specific proteins and promotes their degradation, a process essential for cell regulation and apoptosis. In multiple myeloma (MM) treatment, drugs targeting CRBN, like thalidomide and lenalidomide, show effectiveness by altering substrate specificity of CRBN, targeting tumor-associated proteins for degradation. CRBN-based PROTACs are emerging as promising cancer treatments by directing CRBN to target proteins for degradation. Biocytogen has developed the B-hCRBN mouse model, engineered to express human CRBN instead of the mouse version by inserting the full-length human CRBN CDS into the mouse Crbn exons 2-3. Expression of human CRBN mRNA and proteins were exclusively detected in homozygous humanized mice and these mice also demonstrated increased IL2 production in CD4+ T cells in response to lenalidomide treatment, confirming successful generation of the model. In summary, B-hCRBN mice are effective tool for preclinical in vivo efficacy and safety evaluation of CRBN-targeted drugs, including CRBN-based small molecules, molecular glues, and PROTAC drugs. Citation Format: Mari Kuraguchi, Ying Zhao, Chonghui Liu, Xiao Liu, Jiansu Zhang. The humanized CRBN mice model facilitates PROTACs studies based on CRBN ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7269.