Abstract B027: TNG961: A selective oral molecular glue degrader of HBS1L inducing tumor regression in naïve and PRMT5i-refractory FOCAD-deleted models

Abstract Chromosomal deletion of tumor suppressor genes can lead to collateral loss of nearby genes, creating therapeutic opportunities for synthetic lethal targeting. One example is the frequent co-deletion of MTAP with CDKN2A/B on chromosome 9p, which creates a dependency on PRMT5 for cell survival. Located telomeric to CDKN2A and MTAP is FOCAD, a gene encoding a protein essential for stabilizing the SKI complex. The SKI complex is responsible for degrading aberrant mRNAs, thereby maintaining mRNA homeostasis. Loss of FOCAD disrupts SKI complex function, resulting in ribosome stalling on aberrant mRNA transcripts. These stalled ribosomes are dependent on the HBS1L/PELO complex for rescue and recycling, establishing a synthetic lethal interaction between HBS1L/PELO and FOCAD loss. TNG961 is a first-in-class molecular glue that targets HBS1L for degradation, representing a novel therapeutic strategy for FOCAD-deleted tumors. In vitro, TNG961 treatment leads to a dose-dependent decrease in HBS1L protein levels, which in turn destabilizes the portion of PELO involved in ribosome rescue. TNG961 displays proteome-wide selectivity for HBS1L, with no change in SALL4 protein level as determined by western blot. TNG961-induced HBS1L degradation and PELO destabilization can both be rescued by inactivation of CRBN confirming mechanism, which is further supported by cryoEM data. In engineered HiBiT knock-in cells, treatment with TNG961 induces maximal HBS1L degradation within 4 hours, without affecting GSPT1 protein levels. This selective degradation translates to potent growth inhibition in FOCAD-deleted cells, with ∼100-fold selectivity compared to FOCAD-proficient cells across 5 isogenic pairs. This selective vulnerability is preserved in a large cell line panel of over 90 models. Finally, oral administration of TNG961 induces dose-dependent degradation of HBS1L and subsequent destabilization of PELO protein in FOCAD-deleted xenograft models, resulting in tumor stasis or regression across multiple lineages. Notably, TNG961 remains effective in a pancreatic model that has become refractory to PRMT5 inhibitor treatment, supporting its potential utility in PRMT5i-resistant settings. TNG961 has been nominated as a development candidate and is currently in IND-enabling studies. Citation Format: Katherine Lazarides, Minjie Zhang, Frank J. Bruzzese, Douglas A. Whittington, Charlotte B. Pratt, Lauren Catherine M. Martires, John P. Maxwell, Alice Tsai, Colin Liang, Patrick McCarren, Yong Liu, John Zhang, Matthew R. Tonini, Margaret A. Wyman, Xinyuan Wu, Jannik N. Andersen, Hilary E. Nicholson. TNG961: A selective oral molecular glue degrader of HBS1L inducing tumor regression in naïve and PRMT5i-refractory FOCAD-deleted models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B027.