Self-assembled bottlebrush glue degraders for tumour - targeted protein knockdown

Speaker: Mainak Banerjee, Cancer Institute, Strasbourg, France

Multiple myeloma (MM) is a complex hematologi c malignancy marked by uncontrolled plasma cell proliferation. Despite advances like bi-specific anti bodies, ADCs, CAR-T cells, and protein degraders, no curative treatment exists, and clinical res ponses remain suboptimal. Targeted protein degradation (TPD), including PROTACs and mol ecular glues (MGs), offers a novel approach by eliminating disease-causing proteins. MGs such as  CC-885 and CC-90009 selectively degrade GSPT1, a protein implicated in AML and MM progression,   via the ubiquitin-proteasome system. However, poor pharmacokinetics (PK) and off-target toxicity limit their clinical translation.To address these challenges, we developed MB-276, a novel MG with high predicted affinity for GSPT1. Post-functionalization onto a bottlebrush polymer (BBP@GSPT1) enables selective delivery and in vitro efficacy in MM cell lines. This strategy improves biodistribution and tumor specific uptake while preserving degradation efficiency, offering a promising advance toward translational TPD therapies.