Deborah S. Mortensen, Hunter P. Shunatona, Natalie Holmberg‐Douglas, Jayce Rhodes, Diogo Da Silva, Jim Gamez, Matt Groza, Jinyi Zhu, Andy Christoforou, S.A. Johnson, Godrej Khambatta, Rama Krishna Narla, Roshan Y. Nimje, Dehua Huang, Dharmpal S. Dodd, Jennifer K. Griffin, Giulianna A. Miseo, Brandon Whitefield, Dahlia R. Weiss, James Rader, Elif Kuzu, Jim Leisten, Chon Lai, Lihong Shi, Joselyn Del Rosario, Deepak Dalvie, Mark Rolfe, Christoph W. Zapf, Peter Belmont, Matt Alexander, Neil Bence, Lynda Groocock
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.