TNG961 Is a Selective Oral HBS1L Molecular Glue Degrader for the Treatment of FOCAD-Deleted Cancers.

TNG961 is a potent, selective oral degrader of HBS1L that effectively treats FOCAD-deleted cancers, including PRMT5 inhibitor-refractory models.

• Why it matters: FOCAD deletion occurs in about one-third of MTAP-deleted cancers, creating a vulnerability that can be exploited for targeted therapy. Understanding and targeting this dependency could improve treatment options for these cancers.
• What they did: Researchers screened a focused compound library, identified a cereblon-binding molecule, and developed TNG961, a selective HBS1L degrader guided by cryo-EM and proteomics, to induce degradation and disrupt the HBS1L/PELO complex.
• The result: Oral TNG961 treatment causes tumor regression in FOCAD-negative xenograft models, activates stress responses, and inhibits growth, supporting its potential as a first-in-class precision therapy.