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.