Tango Therapeutics, Inc. · NASDAQ:TNGX
Tango Therapeutics — Botton Champalimaud International Pancreatic Cancer Conference 2025
16 slides from Tango Therapeutics's conference presentation, October 2025
Slide 1: TNG961: Targeting HBS1L for the Treatment of Chr9p21 Deleted Cancers with FOCAD loss
TNG961: Targeting HBS1L for the Treatment of Chr9p21 Deleted Cancers with FOCAD loss Jannik N. Andersen Botton Champalimaud International Pancreatic Cancer Conference, Oct 2025
Slide 2: Disclosures
Disclosures • Jannik N Andersen is an employee and stockholder of Tango Therapeutics. CONFIDENTIAL
Slide 3: Most cancer targets are not drugged yet
Most cancer targets are not drugged yet SYNTHETIC DNA DAMAGE LETHALITY REPAIR TUMOR Primary approach to SUPPRESSOR targeting tumor GENES suppressor gene loss IMMUNE EVASION • Important drivers of cancer (CoREST) inactivated or deleted in almost all human cancers CRISPR TECHNOLOGY • Not directly drug
Slide 4: Targeting Chr9p21 deleted cancers with MTAP and FOCAD loss
Targeting Chr9p21 deleted cancers with MTAP and FOCAD loss ~33% of MTAP-del cancers HBS1L or PELO knockout is are also FOCAD-del synthetic lethal with FOCAD loss HBS1L (TNG961) PRMT5i (TNG462, TNG456) P-value Synthetic lethal with FOCAD loss Effect size MTAP and FOCAD are frequently co-deleted Tango
Slide 5: FOCAD deletion is frequent and occurs in 20-40% of MTAP deleted cancers including ~8% of PDAC
FOCAD deletion is frequent and occurs in 20-40% of MTAP deleted cancers including ~8% of PDAC FOCAD deletion frequency across indications Large patient opportunity • FOCAD loss occurs is present in MPNST 20% Glioblastoma 17% ~20,000 new addressable cancers/yr in Mesothelioma 9% the US* Pancreatic 8%
Slide 6: FOCAD-HBS1L synthetic lethality caused by impaired mRNA homeostasis
FOCAD-HBS1L synthetic lethality caused by impaired mRNA homeostasis HBS1L and FOCAD both participate in ribosome rescue FOCAD-del cells are dependent on HBS1L TNG961 + Dox (HBS1L on) - Dox (HBS1L off) Cells lacking FOCAD rely on HBS1L/PELO for HBS1L knockdown in FOCAD-del ribosome recycling Miapaca2
Slide 7: HBS1L degradation effectively impairs the HBS1L/PELO complex
HBS1L degradation effectively impairs the HBS1L/PELO complex PELO protein level is decreased after HBS1L degradation MIAPACA2 cells with HBS1L-dTAG cDNA and Global proteomics in MM.1s cells treated with an endogenous HBS1L knockout HBS1L molecular glue degrader tool compound 6 hours 24 hours 6 hours
Slide 8: TNG961 is a first-in-class molecular glue degrader targeting HBS1L
TNG961 is a first-in-class molecular glue degrader targeting HBS1L TNG961 Back-to-back target validation papers Development candidate February 2025 AbbVie Broad HBS1L Institute E3 ligase (CRBN) TNG961 Molecular glue GSK (AACR 2025) TANGO • Cryo-EM structure of TNG961 CONFIDENTIAL
Slide 9: TNG961 is an HBS1L-selective molecular glue degrader that causes FOCAD-dependent loss of viability
TNG961 is an HBS1L-selective molecular glue degrader that causes FOCAD-dependent loss of viability Biochemical complex Protein degradation in cells Cellular viability formation Ternary complex formation (%) HBS1L 300 GSPT1 200 100 Reference compound 0 0.0001 0.001 0.01 0.1 1 10 TNG961 (μM) FOCAD nul
Slide 10: TNG961 induces HBS1L degradation in a CRBN-dependent manner in human cell lines
TNG961 induces HBS1L degradation in a CRBN-dependent manner in human cell lines CRBN knockout rescues TNG961-induced NEDDylation inhibition rescues TNG961- HBS1L degradation induced HBS1L degradation Control CRBN knockout Vehicle +100 nM MLN4924 (sgITC) (sgCRBN) 0 1 10 100 1000 0 1 10 100 1000 nM TN
Slide 11: TNG961 has proteome-wide selectivity for HBS1L
TNG961 has proteome-wide selectivity for HBS1L TNG961 selectively degrades HBS1L Summary • 500 nM (>50X DC50), 6 h 10-8 HBS1L treatment, MM.1s cells 10-7 • TNG961 efficiently degrades 10-6 HBS1L without decreasing protein level of any common p-value 10-5 IMiD neosubstrates 10-4 10-3 GSPT1 • SALL4 pr
Slide 12: TNG961 development candidate is potent and selective
TNG961 development candidate is potent and selective Synthetic lethal with FOCAD loss Highlights 7-day viability (92 cell lines) Potency Maximum dose tested DC50 7 nM (0.15 nM free potency) GI50 113 nM (2.5 nM free potency) Selectivity ~100-fold across 5 isogenic cell line pairs FOCAD- FOCAD- FOCAD-
Slide 13: TNG961 causes tumor regressions across diverse in vivo models
TNG961 causes tumor regressions across diverse in vivo models FOCAD-null xenografts Summary RS411 MIAPACA2 MIAPACA2 • TNG961 inhibits tumor growth 2500 RS411 Blood CDX PDAC CDX Vehicle across histologies supporting broad Tumor volume (mm3) Tumor volume (mm3) 2000 1000 2 mpk TNG961 development opport
Slide 14: Preclinical data supports treatment of patients who progress on any PRMT5i and/or upfront combination therapy
Preclinical data supports treatment of patients who progress on any PRMT5i and/or upfront combination therapy MIAPACA2 (FOCAD-null, MTAP-null Pancreatic CDX) (HBS1L) (PRMT5i) CONFIDENTIAL
Slide 15: Summary
Summary TNG961 is an oral, potent and selective development candidate targeting HBS1L FOCAD-deficient tumors • HBS1L/PELO is a synthetic lethal target in FOCAD loss (~4% of cancers) • TNG961: potent, selective HBS1L inhibitor with proteome-wide specificity • Selective growth inhibition in FOCAD-defi
Slide 16: Acknowledgements
Acknowledgements Tango Therapeutics CONFIDENTIAL
Tango Therapeutics — Botton Champalimaud International Pancreatic Cancer Conference 2025 on 6ix