Slide 1: TNG961: a selective, oral HBS1L molecular glue degrader for FOCAD-deleted cancers
TNG961: a selective, oral HBS1L molecular glue degrader for the treatment of FOCAD-deleted cancers Hilary E. Nicholson, Ph.D. Tango Therapeutics, Boston, MA
Slide 2: Disclosure Information
Disclosure Information Hilary E. Nicholson, Ph.D. I have the following relevant financial relationships to disclose: Employee of Tango Therapeutics Stockholder in Tango Therapeutics 1
Slide 3: Wholly-owned pipeline targeting multiple high value indications
Wholly-owned pipeline targeting multiple high value indications PATIENT MOLECULE SELECTION TARGET INDICATIONS CLINICAL TRIALS STATUS PRE-CLINICAL PHASE 1/2 PHASE 3 Pancreatic, MTAP-del Phase 1/2 data PRMT5 Lung, cancers in 2026 non-CNS cancer Vopimetostat (TNG462) MTAP-del/ PRMT5 / Pancreatic, Phase
Slide 4: Multiple synthetic lethality opportunities created by chr9p21 loss
Multiple synthetic lethality opportunities created by chr9p21 loss FOCAD deletion co-occurs with HBS1L is a top dependency in CDKN2A and MTAP loss FOCAD-negative cells TCGA Pan-Cancer Atlas 3
Slide 5: Multiple synthetic lethality opportunities created by chr9p21 loss
Multiple synthetic lethality opportunities created by chr9p21 loss FOCAD deletion co-occurs with FOCAD-negative cells require HBS1L CDKN2A and MTAP loss for ribosome recycling TCGA Pan-Cancer Atlas 4
Slide 6: Multiple synthetic lethality opportunities created by chr9p21 loss
Multiple synthetic lethality opportunities created by chr9p21 loss FOCAD deletion co-occurs with FOCAD-negative cells require HBS1L CDKN2A and MTAP loss for ribosome recycling TCGA Pan-Cancer Atlas 5
Slide 7: Multiple synthetic lethality opportunities created by chr9p21 loss
Multiple synthetic lethality opportunities created by chr9p21 loss FOCAD-negative cells depend on HBS1L for ribosome recycling and survival + HBS1L cDNA - HBS1L cDNA HBS1L knockout in FOCAD-del MIAPACA2 cells ER stress, activation of unfolded protein response, Zhang et al BBA-MCR 2025 loss of cell v
Slide 8: Parallel biochemical and cellular screens identified HBS1L-selective starting points
Parallel biochemical and cellular screens identified HBS1L-selective starting points Tango molecular glue library screened in parallel against HBS1L (target) and GSPT1 (anti-target) 7
Slide 9: Structure-guided design increased HBS1L activity
Structure-guided design increased HBS1L activity TNG-4857 cyclization TNG-7535 TNG-7326 Cryo-EM (2.6 Å resolution) Cellular HiBit TNG-4857 TNG-7535 TNG-7326 HBS1L DC50 (µM), Dmax (%) 0.012, 101 0.001, 69 0.0006, 92 • Cyclization conferred potency benefits GSPT1 DC50 (µM) >10 0.007 > 10 • GSPT1 activ
Slide 10: Structure-guided design increased HBS1L activity
Structure-guided design increased HBS1L activity TNG-4857 cyclization TNG-7535 TNG-7326 Cryo-EM (2.9 Å resolution) Cellular HiBit TNG-4857 TNG-7535 TNG-7326 HBS1L DC50 (µM), Dmax (%) 0.012, 101 0.001, 69 0.0006, 92 GSPT1 DC50 (µM) >10 0.007 > 10 Cellular viability AC50 (µM) 0.737 0.240 0.004 TNG961
Slide 11: Electrostatic and hydrophobic interactions with both HBS1L and CRBN drive TNG961 potency and selectivity
Electrostatic and hydrophobic interactions with both HBS1L and CRBN drive TNG961 potency and selectivity • All three urea heteroatoms interact with CRBN – key pharmacophore • HBS1L R664 interacts with CRBN E377 forming a larger pocket than the analogous GSPT1 residues • Pocket accommodates gem- dime
Slide 12: TNG961 has proteome-wide selectivity for HBS1L and only impairs viability of FOCAD-negative cells
TNG961 has proteome-wide selectivity for HBS1L and only impairs viability of FOCAD-negative cells Selective degradation of HBS1L FOCAD-dependent efficacy HBS1L GSPT1 GSPT2 CK1α Ikaros Aiolos Helios Β-actin 12 6 h, MM.1s
Slide 13: Oral TNG961 induces dose-dependent HBS1L degradation in vivo
Oral TNG961 induces dose-dependent HBS1L degradation in vivo Dose-proportional PK Efficient HBS1L degradation in tumors 13
Slide 14: TNG961 demonstrates broad activity across indications
TNG961 demonstrates broad activity across indications Efficacy in FOCAD-negative xenografts Broad development opportunity • Efficacy observed across CDX models from different histologies • Complete regression observed in models representing high unmet medical need (PDAC and NSCLC) 14
Slide 15: TNG961 has non-overlapping sensitivity with MTA-cooperative PRMT5 inhibitors
TNG961 has non-overlapping sensitivity with MTA-cooperative PRMT5 inhibitors TNG961 regresses tumors that progress on PRMT5i treatment Distinct mechanism MIAPACA2 MTAP-negative, FOCAD-negative PDAC CDX • Data suggest patients who become refractory to PRMT5i may benefit from TNG961 monotherapy MIAPAC
Slide 16: TNG961 + MTA-cooperative PRMT5 inhibitor drives strong combination benefit
TNG961 + MTA-cooperative PRMT5 inhibitor drives strong combination benefit Complete responses observed with TNG961 + vopimetostat combination NCI-H838 MTAP-negative, FOCAD-negative NSCLC CDX 16 TNG961 and vopimetostat (TNG462) dosed sub-therapeutically
Slide 17: TNG961 induces translational arrest and stress response selectively in FOCAD-negative cells
TNG961 induces translational arrest and stress response selectively in FOCAD-negative cells Activation of Activation of Decreased protein translation integrated stress response unfolded protein response TNG961 (µM): 0 0.1 1 0 0.1 1 HBS1L IFRD1 Vinculin Similar data observed for ATF4 17
Slide 18: GLP studies support FIH at efficacious starting dose with ample safety margin
GLP studies support FIH at efficacious starting dose with ample safety margin All nonclinical safety findings reversible and monitorable Predicted TNG961 Human PK 14-Day Exploratory Studies (Rat & NHP) Estimate • Minimal, non-adverse findings CL • No cardiovascular (ECG) signals 1.6 (ml/min/kg) • HB
Slide 19: TNG961 attributes support selection as development candidate
TNG961 attributes support selection as development candidate 19
Slide 20: Broad clinical development opportunity for TNG961 in FOCAD-deleted solid tumors
Broad clinical development opportunity for TNG961 in FOCAD-deleted solid tumors Monotherapy Combination • ~4% of all human cancers are FOCAD deleted • All FOCAD-deleted tumors are also MTAP- (~20,000 new metastatic cases per year in US) deficient, creating opportunity for - ~5% of lung cancer is FOC
Slide 21: TNG961 is an IND-ready, oral, potent, and selective HBS1L degrader for FOCAD deleted cancers
TNG961 is an IND-ready, oral, potent, and selective HBS1L degrader for FOCAD deleted cancers • The HBS1L/PELO complex is a synthetic lethal target on chr9p21 − Approximately 1/3 of all MTAP-deleted tumors are also FOCAD-deleted HBS1L TNG961 • TNG961 is a first-in-class molecular glue degrader target
Slide 22: Acknowledgements
Acknowledgements Tango Therapeutics Cancer Discovery: Nicholson et al. TNG961 is a selective oral HBS1L molecular glue degrader for the treatment of FOCAD-deleted cancers Visit AACR posters: #2983, #3090 and #484 22