Discovery of BRD9 PROTAC/IMiD Bifunctional Molecules as Potent Therapeutics for Hematologic Malignancies

Abstract Bromodomain-containing protein 9 (BRD9) has emerged as an epigenetic target in hematologic malignancies. However, previous studies on BRD9 PROTACs reported MYC upregulation following chronic administration. Here, we describe bifunctional BRD9 PROTAC/immunomodulatory drug (IMiD) degraders engineered to simultaneously eliminate BRD9 and IKZF1. Utilizing ternary complex modeling and structure–activity relationship (SAR) analysis, aromatic linkers and modified E3 ligands facilitated efficient degradation. The lead candidate, B8, induces potent and selective degradation of both BRD9 (DC50 = 57 pM) and IKZF1 (DC50 = 62 pM). B8 showed broad antiproliferative activity across hematologic malignancy cells, particularly lymphomas. In the OCI-ly10 xenograft model, B8 achieved near-complete tumor regression (TGI > 99%), significantly outperforming the selective BRD9 PROTAC E5 (TGI = 31%), without detectable toxicity or MYC upregulation. These findings validate this dual-targeting PROTAC/IMiD strategy as an effective approach to overcoming the limitations of selective BRD9 degraders, underscoring its therapeutic potential in hematologic malignancies.