Data from TNG961 Is a Selective Oral HBS1L Molecular Glue Degrader for the Treatment of FOCAD-Deleted Cancers
Year: 2026
Type: other
Abstract: When tumor suppressor genes are lost through chromosomal deletion, the deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the chr9p21 tumor suppressor gene CDKN2A, creating a synthetic lethal dependency on protein arginine methyltransferase 5 (PRMT5). Telomeric to MTAP lies focadhesin (FOCAD), whose loss induces dependency on the HBS1-like translational GTPase (HBS1L)–protein pelota homolog (PELO) ribosome rescue complex for translational maintenance. FOCAD is deleted in ∼1 out of 3 MTAP-deleted cancers. We screened an immunomodulatory imide drug (IMiD)-focused diversity library and identified a weak hit that bound cereblon (CRBN), 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 the clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic. Significance: FOCAD deletion, frequently co-occurring with MTAP/CDKN2A loss, creates a synthetic lethal dependency on the HBS1L–PELO ribosome rescue complex. TNG961, a first-in-class molecular glue degrader of HBS1L, enforces translational arrest and drives tumor regressions in FOCAD-negative models, including PRMT5 inhibitor-refractory tumors, establishing a novel precision oncology strategy for chromosome 9p21 co-deletion contexts.
Authors: Hilary 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 W. 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W7204937680