9YA9
Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BMS-986458 (local refined), a potent and selective BCL6 ligand directed degrader (LDD)
This is a non-PDB format compatible entry.
Summary for 9YA9
| Entry DOI | 10.2210/pdb9ya9/pdb |
| EMDB information | 72725 |
| Descriptor | B-cell lymphoma 6 protein, Protein cereblon, (3R)-3-(6-{[(3R,4R)-1-{5-chloro-4-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]pyrimidin-2-yl}-3-methylpiperidin-4-yl]amino}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione, ... (4 entities in total) |
| Functional Keywords | cereblon, bcl6, ldd, degrader, e3, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 87139.24 |
| Authors | |
| Primary citation | Mortensen, D.S.,Shunatona, H.P.,Holmberg-Douglas, N.,Rhodes, J.,Da Silva, D.,Gamez, J.,Groza, M.,Zhu, J.,Christoforou, A.,Johnson, S.A.,Khambatta, G.,Narla, R.K.,Nimje, R.Y.,Huang, D.,Dodd, D.S.,Griffin, J.,Miseo, G.,Whitefield, B.,Weiss, D.R.,Rader, J.,Kuzu, E.,Leisten, J.,Lai, C.,Shi, L.,Del Rosario, J.,Dalvie, D.,Rolfe, M.,Zapf, C.W.,Belmont, P.,Alexander, M.,Bence, N.,Groocock, L. 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. J.Med.Chem., 2026 Cited by PubMed Abstract: 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. PubMed: 41670385DOI: 10.1021/acs.jmedchem.5c03123 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.09 Å) |
Structure validation
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