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TitleTNG961 is a selective oral HBS1L molecular glue degrader for the treatment of FOCAD-deleted cancers.
Journal, issue, pagesCancer Discov, Year 2026
Publish dateApr 19, 2026
AuthorsHilary E Nicholson / Douglas A Whittington / Frank J Bruzzese / Katherine Lazarides / Lauren Catherine M Martires / Matthew R Tonini / Helena N Jenkins / Minjie Zhang / Preksha Shahagadkar / Charlotte B Pratt / Kimberly J Briggs / Patrick McCarren / Alice Tsai / Madhavi Bandi / Chengyin Min / Alan Huang / Hongxiang Zhang / Samuel R Meier / Binzhang Shen / Yi Yu / Colin Liang / Yong Liu / Teng Teng / John Zhang / Adam Crystal / William D Mallender / Xinyuan Edward Wu / John P Maxwell / Jannik N Andersen /
PubMed AbstractWhen 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 ...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.
External linksCancer Discov / PubMed:42001523
MethodsEM (single particle)
Resolution2.6 - 2.9 Å
Structure data

75038

10ay

EMDB-75038, PDB-10ay:
Cryo-EM structure of CRBN-DDB1 in complex with HBS1L and TNG961
Method: EM (single particle) / Resolution: 2.9 Å

75840

11mr

EMDB-75840, PDB-11mr:
Cryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (focused refinement)
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

PDB-1c4s:
CHONDROITIN-4-SULFATE. THE STRUCTURE OF A SULFATED GLYCOSAMINOGLYCAN

ChemComp-ZN:
Unknown entry

PDB-1c9w:
CHO REDUCTASE WITH NADP+

Source
  • homo sapiens (human)
KeywordsCYTOSOLIC PROTEIN / FOCAD / ribosome / PELO / ubiquitin

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