Abstract Loss of tumor suppressor genes frequently results in co-deletion of neighboring genes, generating tumor-specific collateral vulnerabilities. On chromosome 9p21, deletion of CDKN2A/B commonly extends to loss of the adjacent MTAP gene creating a known dependency on PRMT5. Telomeric to MTAP lies FOCAD, which is co-deleted in 20-40% of MTAP-deleted cancers. Through unbiased combinatorial and genome-wide CRISPR screens, we discovered that loss of FOCAD, whose protein product stabilizes the SKI complex to maintain mRNA homeostasis, creates a pronounced dependency on the HBS1L/PELO ribosome rescue complex for translational integrity. To exploit this vulnerability, we developed TNG961, a first-in-class, orally bioavailable molecular glue degrader that selectively targets HBS1L. TNG961 induces formation of an HBS1L-TNG961-CRBN ternary complex, leading to potent degradation of HBS1L and secondary destabilization of its binding partner PELO. A 2. 9 Å cryo-EM structure reveals the molecular glue binding mode underlying this tricomplex. A genome-wide drug anchor screen confirmed strict CRBN-dependence and SKI-complex-based sensitivity to TNG961, with proteomic profiling demonstrating exquisite selectivity for HBS1L. Functionally, TNG961 induces robust growth inhibition selectively in FOCAD-deficient models with ∼100-fold selectivity across 5 isogenic cell line pairs. This selective vulnerability is preserved in a larger parental cell line panel of 90 lines (7-day CellTiter-Glo assay) and further supported by a multiplexed PRISM screen of 900 models. Mechanistically, TNG961 induces translational arrest, activation of the unfolded protein response, and growth inhibition selectively in FOCAD-deficient models. In vivo, oral administration of TNG961 drives dose-dependent degradation of HBS1L and produces tumor stasis or regression across multiple FOCAD-deficient xenograft models and tumor histologies, including in the PRMT5 inhibitor-refractory setting. Because FOCAD is located on the antisense DNA strand relative to CDKN2A/B, we investigated the functional impact of partial truncations of FOCAD and translated these findings toward a prospective biomarker strategy for patient selection. IND-enabling studies are complete with a clean safety profile supporting a starting dose within the active range. These data establish targeted degradation of HBS1L as a novel therapeutic approach for FOCAD-deficient cancers and expand the landscape of actionable vulnerabilities arising from 9p21 tumor-suppressor loss. Citation Format: Douglas A. Whittington, Frank J. Bruzzese, Charlotte B. Pratt, Preksha Shahagadkar, Lauren Catherine M. Martires, Alice Tsai, John P. Maxwell, Katherine Lazarides, Matthew R. Tonini, Minjie Zhang, Samuel R. Meier, Colin Liang, Patrick McCarren, Yong Liu, John Zhang, Margaret A. Wyman, Yi Yu, Adam S. Crystal, Ed Wu, Jannik N. Andersen, Hilary Elaine Nicholson. TNG961: A selective oral molecular glue degrader of HBS1L for the treatment of FOCAD-deficient cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND03.
Whittington et al. (Fri,) studied this question.