9DJX
Ternary complex structure of Cereblon-DDB1 bound to WIZ(ZF7) and the molecular glue WIZ-6
This is a non-PDB format compatible entry.
Summary for 9DJX
| Entry DOI | 10.2210/pdb9djx/pdb |
| Related | 9DJT |
| Descriptor | Protein cereblon, DNA damage-binding protein 1, Protein Wiz, ... (7 entities in total) |
| Functional Keywords | cereblon, ligase, molecular glue, degradation |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 280557.49 |
| Authors | Partridge, J.R.,Ma, X.,Ornelas, E. (deposition date: 2024-09-07, release date: 2024-11-27, Last modification date: 2024-12-11) |
| Primary citation | Kerrigan, J.R.,Thomsen, N.M.,Cernijenko, A.,Kochanek, S.E.,Dewhurst, J.,O'Brien, G.,Ware, N.F.,Sanchez, C.C.,Manning, J.R.,Ma, X.,Ornelas, E.,Savage, N.A.,Partridge, J.R.,Patterson, A.W.,Lam, P.,Dales, N.A.,Bonazzi, S.,Borikar, S.,Hinman, A.E.,Ting, P.Y. Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease. J.Med.Chem., 67:20682-20694, 2024 Cited by PubMed Abstract: Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of , a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and exposure. In an hNBSGW mouse xenograft model, demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease. PubMed: 39541509DOI: 10.1021/acs.jmedchem.4c02251 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.35 Å) |
Structure validation
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