Tango Therapeutics, Inc. · NASDAQ:TNGX
Tango Therapeutics — Technical Presentation (November 2025)
18 slides from Tango Therapeutics's technical presentation, Nov 4, 2025
Slide 1: Hit finding and assay enablement for MGAT1, a novel glycosyltransferase
Hit finding and assay enablement for MGAT1, a novel glycosyltransferase involved in cancer cell immune evasion Kasia Handing, Associate Director 2025.11.04
Slide 2: MGAT1 knockout re-sensitizes STK11-mutant mouse tumors to immune checkpoint blockade
MGAT1 knockout re-sensitizes STK11-mutant mouse tumors to immune checkpoint blockade In vivo CRISPR screen AACR 2024 Presentation MGAT1 HDAC1 False Discovery Rate STK11 specific sensitization to Dr. Carolyn R Bertozzi immune checkpoint blockade MGAT1, an essential N-glycosyltransferase, is a top hit
Slide 3: High-quality protein produced to support drug discovery
High-quality protein produced to support drug discovery SDS-Page LC-MS 100KD 70KD 50KD 40KD Biotinylated-Avi-(GS)*7- N-terminally truncated, Theoretical MW (Da) MGAT1(A104-N445 end) 30KD 42880.3 biotinylated, AVI-tagged MGAT1 20KD M = Marker Lane 1 = 2 μg used in SPR assay. Lane 2 = 10 μg M 1 2 Prot
Slide 4: MGAT1 transfers N-acetylglucosamine to its MAN5 substrate producing UDP
MGAT1 transfers N-acetylglucosamine to its MAN5 substrate producing UDP as a product MGAT1 catalyzes first and rate-limiting step of N- UDP production can be measured in UDP-Glo glycan branching pathway biochemical assay UDP-GlcNAc UDP MGAT1 Man5 Man5-GlcNAc Mannose N-Acetylglucosamine MGAT1 UDP + R
Slide 5: Expanded biophysical toolbox developed for characterization of compounds engaging MGAT1
Expanded biophysical toolbox developed for characterization of compounds engaging MGAT1 Detail molecular interactions Thermal stability assessment X-ray crystallography DSF R115 Fluorescence Cmpd TM Mean D211 Sample (°C) C113 49.5 I111 5% DMSO Mn2+ 20 30 40 50 60 70 80 90 100 100 µM binder 55.8 C143
Slide 6: UDP used as a positive control for SPR assay development
UDP used as a positive control for SPR assay development Principle Running conditions Positive control - UDP Relative response (RU) Sensor chip: SA UDP Instrument: Biacore S200 Temperature: 20°C Flow parameters: UDP − Flow rate = 30 μl/min Time (s) − Association time = 90 s MGAT1 MGAT1 Relative resp
Slide 7: Novel small-molecule compounds targeting MGAT1 can be identified in activity and binding screens
Novel small-molecule compounds targeting MGAT1 can be identified in activity and binding screens Biochemical HTS Biophysical DEL Screen 500k Tango Library 3-billion compound library DEL affinity selection Primary Screen PCR amplification Hit confirmation High Throughput DNA sequencing Dose response
Slide 8: SAR development of MGAT1 HTS compound series results in nanomolar inhibitors
SAR development of MGAT1 HTS compound series results in nanomolar inhibitors Correlation between enzymatic inhibition HTS 1 TNG-9333 TNG-2673 and binding affinities MGAT1 UDP-GloTM IC50 1000 197 0.814 0.043 (µM) (y = x) 100 MGAT1 SPR SPR KD (μM) Steady-state KD (µM) 32.2 0.38 0.07 10 Kinetic KD (µM)
Slide 9: Are identified compounds orthostatic binders?
Are identified compounds orthostatic binders? What do we expected if hits compete with UDP for What do we expected if hits do not compete with binding? UDP for binding? UDP UDP Comp UDP UDP MGAT1 MGAT1 MGAT1 MGAT1 Comp When competing with UDP, KD should be weaker as When binding to different site th
Slide 10: HTS compound TNG-9333 binds in allosteric pocket
HTS compound TNG-9333 binds in allosteric pocket TNG-9333 - Direct binding Relative response (RU) Relative response (RU) KD: 0.4 µM Time (s) TNG-9333 Conc (M) TNG-9333 – Competition with UDP (5000 μM) Relative response (RU) Relative response (RU) KD: 0.2 µM Time (s) TNG-9333 Conc (M) Runs were perfo
Slide 11: HTS compound TNG-9333 binds in allosteric pocket
HTS compound TNG-9333 binds in allosteric pocket TNG-9333 - Direct binding UDP - Direct binding Relative response (RU) Relative response (RU) Relative response (RU) Relative response (RU) KD: 0.4 µM KD: 22 µM Time (s) TNG-9333 Conc (M) Time (s) UDP Conc (M) TNG-9333 – Competition with UDP (5000 μM)
Slide 12: Additive thermal stabilization effect observed by HTS compound and UDP binding in DSF assay
Additive thermal stabilization effect observed by HTS compound and UDP binding in DSF assay Fluorescence 5% DMSO 5000 μM UDP 100 μM HTS TNG-9333 100 μM HTS TNG-9333 + 5000 μM UDP 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperature (ºC) Sample Name TM Mean (°C) △TM (°C) 5000 μM UDP 51 2 D
Slide 13: DEL-1 compound binds in allosteric pocket and competes with HTS compound but not UDP
DEL-1 compound binds in allosteric pocket and compete for binding with HTS compound but not UDP Direct binding Relative response (RU) Relative response (RU) KD: 1.1 µM Time (s) DEL-1 Conc (M) Competition with UDP (5000 μM) DSF orthogonal validation TM Mean (°C) △TM (°C) Relative response (RU) Relati
Slide 14: DEL-1 compound binds in allosteric pocket and competes with HTS compound but not UDP
DEL-1 compound binds in allosteric pocket and compete for binding with HTS compound but not UDP Direct binding Relative response (RU) Relative response (RU) KD: 1.1 µM Time (s) DEL-1 Conc (M) Competition with UDP (5000 μM) Competition with TNG-9333 (20 μM) Relative response (RU) Relative response (R
Slide 15: Structural biology confirms allosteric binding of HTS and DEL compounds
Structural biology confirms allosteric binding of HTS and DEL compounds UDP UDP Active site Active site TNG-9333 Allosteric site DEL 1 Allosteric site 2.0 Å resolution 1.3 Å resolution 15 CONFIDENTIAL
Slide 16: Summary
Summary • MGAT1 is a novel, druggable, and tractable immune evasion target in STK11-mutant cancers • Robust protein production, biophysical/biochemical assays established • First human MGAT1 co-crystal structure solved • Novel chemical matter identified via orthogonal approaches yielding nanomolar i
Slide 17: Acknowledgements
Acknowledgements Tango Therapeutics CRO Partners HitGen Inc. Biortus Biosciences Wuxi AppTec We gratefully acknowledge the contributions from all Tango associates, members of the MGAT1 Project Team, the DEL Working Group members, as well as the contributions from our CRO partners 17 CONFIDENTIAL
Slide 18: Tango Therapeutics
Ej TANGO therapeutics CONFIDENTIAL
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