TNG961

TNG961 is a selective and orally active CRBN-mediated HBS1L molecular glue degrader. TNG961 induces formation of an HBS1L-TNG961-CRBN ternary complex, leading to potent degradation of HBS1L and secondary destabilization of its binding partner PELO. TNG961 can reduce HBS1L protein levels, thereby disrupting the PELO region involved in ribosome rescue. TNG961 can be used for the study of FOCAD-deficient cancers, such as pancreatic cancer ^[1].

In Vivo, TNG961 (Oral administration) 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^[1].

In Vitro, In vitro, TNG961 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^[1]. In engineered HiBiT knock-in cells, treatment with TNG961 induces maximal HBS1L degradation within 4 hours, without affecting GSPT1 protein levels^[1].

References:
[1]. Katherine Lazarides, et al. Abstract B027: TNG961: A selective oral molecular glue degrader of HBS1L inducing tumor regression in naïve and PRMT5i-refractory FOCAD-deleted models. Mol Cancer Ther (2025) 24 (10_Supplement): B027.
[2]. Douglas A. Whittington, et al. Abstract ND03: TNG961: A selective oral molecular glue degrader of HBS1L for the treatment of FOCAD-deficient cancers. Cancer Res (2026) 86 (8_Supplement): ND03.