11MR
Cryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (focused refinement)
This is a non-PDB format compatible entry.
Summary for 11MR
| Entry DOI | 10.2210/pdb11mr/pdb |
| EMDB information | 75840 |
| Descriptor | HBS1-like protein, Protein cereblon, ZINC ION, ... (4 entities in total) |
| Functional Keywords | focad, pelo, ribosome, ubiquitin, cytosolic protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 139850.43 |
| Authors | |
| Primary citation | Nicholson, H.E.,Whittington, D.A.,Bruzzese, F.J.,Lazarides, K.,Martires, L.C.M.,Tonini, M.R.,Jenkins, H.N.,Zhang, M.,Shahagadkar, P.,Pratt, C.B.,Briggs, K.J.,McCarren, P.,Tsai, A.,Bandi, M.,Min, C.,Huang, A.,Zhang, H.,Meier, S.R.,Shen, B.,Yu, Y.,Liang, C.,Liu, Y.,Teng, T.,Zhang, J.,Crystal, A.,Mallender, W.D.,Wu, X.E.,Maxwell, J.P.,Andersen, J.N. TNG961 is a selective oral HBS1L molecular glue degrader for the treatment of FOCAD-deleted cancers. Cancer Discov, 2026 Cited by PubMed Abstract: When tumor suppressor genes are lost through chromosomal deletion, deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the Chr9p21 tumor suppressor gene CDKN2A, creating synthetic lethal dependency on PRMT5. Telomeric to MTAP lies FOCAD, whose loss induces dependency on the HBS1L/PELO ribosome-rescue complex for translational maintenance. FOCAD is deleted in ~1/3 of MTAP-deleted cancers. We screened an IMiD-focused diversity library and identified a weak hit that bound cereblon, promoted HBS1L-CRBN-compound complex formation, and induced E3-ligase-dependent HBS1L ubiquitination and degradation. Guided by cryo-EM structures and proteome selectivity we developed TNG961, a potent, selective HBS1L degrader that disrupts the HBS1L/PELO complex, inducing translational arrest, unfolded protein response activation, and growth inhibition in FOCAD-negative models. Oral administration of TNG961 regresses FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models, establishing HBS1L degradation as a strategy to exploit FOCAD loss and supporting clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic. PubMed: 42001523DOI: 10.1158/2159-8290.CD-26-0040 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.6 Å) |
Structure validation
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