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

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.