Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Technical Presentation (April 2023)
16 slides from Foghorn Therapeutics's technical presentation, Apr 13, 2023
Slide 1: Targeting Transcription Factor – BAF Interactions in Cancer
Targeting Transcription Factor – BAF Interactions in Cancer Asad Taherbhoy 04/13/23 Company Confidential & Proprietary Information
Slide 2: Drugging Transcription Factors
Drugging Transcription Factors TFs are compelling drug targets… • Highly involved in gene expression • Implicated in range of cancers and other diseases …but historically difficult to target • Featureless surface: no druggable binding pocket TF • Challenges with drugging charged DNA-protein interact
Slide 3: BAF controls chromatin accessibility
BAF controls chromatin accessibility Company Confidential & Proprietary Information 3
Slide 4: Drugging Transcription Factors
Drugging Transcription Factors TFs are compelling drug targets… Foghorn’s Focus • Highly involved in gene expression • Implicated in range of cancers and other Potential diseases druggable sites …but historically difficult to target BAF • Featureless surface: no druggable binding pocket TF • Challen
Slide 5: SPI1 (PU.1) transcription factor known to control Hematopoiesis
SPI1 (PU.1) transcription factor known to control Hematopoiesis Dependency NGS based on the TF and Co-IPs S.H. Orkin and L.I. Zon, Cell 2008 approaches BAF activity Company Confidential & Proprietary Information 5
Slide 6: Validating the SPI-BAF collaboration in AML
Validating the SPI-BAF collaboration in AML SPI1 Expression vs. Dependency ATAC-seq +/- BAF Dual Inhibitor Co-IP: SPI1 and BAF SPI1 RNA levels (log2(TPM)) SPI1 CERES CRISPR Dependency Score BAF Dual Inhibitor Treatment RNA-seq: SPI1 Target Genes Company Confidential & Proprietary Information 6
Slide 7: Foghorn’s approach to targeting TF-BAF interactions
Foghorn’s approach to targeting TF-BAF interactions Foghorn’s Focus Potential druggable sites BAF TF Protein Validation of TF- Mapping TF Assays/HTS Generation BAF Interaction Binding Site Company Confidential & Proprietary Information 7
Slide 8: Foghorn can generate BAF/BAF components with high purity and at scale
Foghorn can generate BAF/BAF components with high purity and at scale Catalytic Core Sub-complexes Subunits Full BAF Structural Core Full BAF Structural Core Catalytic Core SEC: Full BAF 8
Slide 9: Validating the SPI1-BAF interaction in vitro
Validating the SPI1-BAF interaction in vitro Full BAF-SPI AUC Full BAF-SPI TR-FRET Pull-down Assay Structural Core Catalytic Core Input beads SPI1 Input beads SPI1 SPI KD = 1.4uM KD = 2.4uM SPI SPI Company Confidential & Proprietary Information 9
Slide 10: The reductionist approach: determining where SPI1 binds on BAF
The reductionist approach: determining where SPI1 binds on BAF SBR = SPI Binding Region Pull-Down Assay Mass Spec. Footprinting SPI SPI Proteolysis LC-MS/MS Proteolysis LC-MS/MS SPI Labeling time SPI 𝒌𝒍𝒂𝒃𝒆𝒍𝒊𝒏𝒈(𝑩𝑨𝑭) 𝐏𝐫𝐨𝐭𝐞𝐜𝐭𝐢𝐨𝐧 𝐑𝐚𝐭𝐢𝐨 = 𝒌𝒍𝒂𝒃𝒆𝒍𝒊𝒏𝒈(𝑩𝑨𝑭: 𝑻𝑭)…
Slide 11: The reductionist approach: determining where SPI1 binds on BAF
The reductionist approach: determining where SPI1 binds on BAF SBR = SPI Binding Region Pull-Down Assay Mass Spec. Footprinting SPI SPI TF2 TF3 SPI TF4 SPI SPI Various TFs map to different surfaces on BAF SBR SPI Company Confidential & Proprietary Information 11
Slide 12: The reductionist system recapitulates the affinity of SPI1 for Full BAF
The reductionist system recapitulates the affinity of SPI1 for Full BAF Full BAF SBR △SBR SPI SPI ITC: SBR-SPI binding SPI SBR-SPI TR-FRET Full BAF-SPI AUC SBR SBR TR-FRET ratio △SBR △SBR KD = 1.4uM SBR titration (nM) KD = 2.4uM SBR KD = 1.65 uM Company Confidential & Proprietary Information 12
Slide 13: Validating the reductionist system in context of the BAF Structural Core
Validating the reductionist system in context of the BAF Structural Core Full BAF SPI-Structural Core Binding SPI Structural Core △SBR Structural Core Structural Core △SBR Structural Core SPI Structural Core - SBR competition SPI SBR △SBR SPI SBR IC50 = 500nM SBR SPI △SBR Company Confidential & Prop
Slide 14: A specific domain within SPI is responsible for binding to BAF
A specific domain within SPI is responsible for binding to BAF Full BAF ITC: SBR-SPI vs. SBR-SPI Domain SPI KD = 1.26uM SPI SPI Domain KD = 1.07 uM SPI SBR-SPI SBR-SPI Domain SPI SBR SBR SPI SPI Domain Company Confidential & Proprietary Information 14
Slide 15: Variety of screening options for finding inhibitors of SPI-BAF
Variety of screening options for finding inhibitors of SPI-BAF SBR SPI SPI SPI SPI SBR SPI Domain SPI Domain SPI Domain SPI Domain Complexity Simplified system Allostery Robust assay setup TF-FRET AlphaLISA DELFIA FP Company Confidential & Proprietary Information 15
Slide 16: Acknowledgements: Foghorn Team
Acknowledgements: Foghorn Team Company Confidential & Proprietary Information 16
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