Discovery of BMS-986458, a Potent and Selective B-Cell Lymphoma 6 Protein Ligand-Directed Degrader, for the Treatment of B-Cell Non-Hodgkin Lymphoma.

B-cell lymphoma 6 protein (BCL6) is an oncogenic driver dysregulated and overexpressed in subtypes of high-risk non-Hodgkin lymphoma (NHL). Development of agents that induce the targeted degradation of BCL6 would offer a promising novel therapeutic approach. For this purpose, we employed ligand-directed degraders, heterobifunctional molecules linking a BCL6-binding ligand to a cereblon recruiter, enabling cereblon-mediated BCL6 degradation. Through a focused optimization effort, we identified highly potent BCL6 degraders, culminating in the selection of BMS-986458 for clinical development. BMS-986458 induces rapid cereblon-dependent BCL6 degradation while sparing known CRBN neosubstrates such as CK1α, GSPT1, Aiolos, Ikaros, or SALL4. Oral administration of BMS-986458 results in dose-dependent pharmacokinetics, pharmacodynamics, and significant antitumor efficacy in mouse models of lymphoma. A potential first-in-class agent, BMS-986458, is currently being evaluated in a phase 1/2 clinical trial (NCT06090539) for patients with relapsed/refractory NHL.