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TitleDiscovery of BMS-986458, a Potent and Selective B-Cell Lymphoma 6 Protein Ligand-Directed Degrader, for the Treatment of B-Cell Non-Hodgkin Lymphoma.
Journal, issue, pagesJ Med Chem, Year 2026
Publish dateFeb 11, 2026
AuthorsDeborah S Mortensen / Hunter P Shunatona / Natalie Holmberg-Douglas / Jayce Rhodes / Diogo Da Silva / Jim Gamez / Matt Groza / Jinyi Zhu / Andy Christoforou / Scott A Johnson / Godrej Khambatta / Rama Krishna Narla / Roshan Y Nimje / Dehua Huang / Dharmpal S Dodd / Jennifer Griffin / Giulianna 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 /
PubMed AbstractB-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 ...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.
External linksJ Med Chem / PubMed:41670385
MethodsEM (single particle)
Resolution3.09 Å
Structure data

72725

9ya9

EMDB-72725, PDB-9ya9:
Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BMS-986458 (local refined), a potent and selective BCL6 ligand directed degrader (LDD)
Method: EM (single particle) / Resolution: 3.09 Å

Chemicals

PDB-1ctu:
TRANSITION-STATE SELECTIVITY FOR A SINGLE OH GROUP DURING CATALYSIS BY CYTIDINE DEAMINASE

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsLIGASE / Cereblon / BCL6 / LDD / degrader / E3

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