TNG961 (TNG-961) is a potent, selective and oral CRBN-dependent HBS1L (GSPT3) molecular glue degrader with DC50 of 7 nM and Dmax of 98%, does not affect closely related GSPT1 protein, disrupts the HBS1L/PELO complex.
TNG961 selectively promotes ternary complex formation between Cullin 4A (Cul4A)-RING-box protein 1 (Rbx1)-DNA damage-binding protein (DDB1)-CRBN and HBS1L in a dose-dependent manner with AC50 of 14.7 nM, compared with an AC50 value > 10 µM for GSPT1.
TNG961 induces proximal association of HBS1L with a functional CRBN E3 ligase complex, with high selectivity over GSPT1.
TNG961 promotes ATP-dependent poly-ubiquitination of HBS1L, but not GSPT1.
TNG961 induces CRBN-dependent endogenous HBS1L degradation with proteome wide selectivity.
TNG961 inhibits viability of FOCAD-negative NCIH1755 cells with a potency of 100 nM, while does not affect FOCAD-reconstituted cells up to 10 uM.
TNG961 induces translational arrest and activation of the unfolded protein response (UPR) in FOCAD-negative, but not FOCAD-positive cells.
TNG961 induces tumor regressions across multiple FOCAD-negative xenograft models from diverse histologies and retained activity in tumors progressing on PRMT5 inhibitor treatment.