Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — AACR April 2026
24 slides from Foghorn Therapeutics's conference presentation, April 2026
Slide 1: Pharmacologic Disruption of Chromatin Regulatory Factors: ARID1B and SMARCA2
Pharmacologic Disruption of Chromatin Regulatory Factors: ARID1B and SMARCA2 Steven Bellon, Ph.D. Foghorn Therapeutics, Watertown MA
Slide 2: Disclosure Information
Disclosure Information Steven Bellon, Ph.D. I have the following relevant financial relationships to disclose: Employee of: Foghorn Therapeutics Stockholder in: Foghorn Therapeutics I have no other financial relationships to disclose.
Slide 3: Chromatin Regulatory System Orchestrates Gene Expression
Chromatin Regulatory System Orchestrates Gene Expression: Multiple Opportunities for Targets and Therapeutics Chromatin Regulatory System genes are implicated across a wide range of cancers Chromatin Remodeling Complexes – specialized multiprotein machines that Chromatin – compacted Transcription Fa
Slide 4: Foghorn is Focused on Some of the Most Relevant Genes in Cancer
Foghorn is Focused on Some of the Most Relevant Genes in Cancer Most Frequently Mutated Genes in Human Cancer Foghorn Focus Foghorn Focus 4 | Mendiratta G, et al. Nature Communications (2021)
Slide 5: Selective ARID1B Targeting Unlocks Synthetic Lethal Strategy for ARID1A Mutant Cancers
Selective ARID1B Targeting Unlocks Synthetic Lethal Strategy for the Treatment of ARID1A Mutant Cancers Synthetic Lethal Relationship Between ARID1A and ARID1B Knockout Inhibits Cell Growth in ARID1A ARID1B Mutant Cancer Cells ES2 EFE-184 (ARID1A WT) (ARID1A Null) Non-targeting sgRNA PCNA Knockout A
Slide 6: ARID1B: Drugging A Previously Undruggable Target
ARID1B: Drugging A Previously Undruggable Target ARID1A/B Drug Targeting Considerations BAF Nucleosome • Large and highly unstructured protein ~ 240 kDa • No known enzymatic function • Member of large, multi-subunit complex • High sequence homology (~60%) to ARID1A Approach • Discover binders to ARI
Slide 7: Foghorn Platform Yields Several Selective ARID1B Binder Series
Foghorn Platform Yields Several Selective ARID1B Binder Series SERIES A SERIES B ARID1B ARID1A Binding ARID1A >2x selectivity for ARID1B KD= 25.3 ± 3.4 µM N= 0.90 ± 0.02 ARID1B ARID1B Binding ARID1A 7 |
Slide 8: Structure-Based Optimization Drives Improved ARID1B Binding Affinity
Structure-Based Optimization Drives Improved ARID1B Binding Affinity From 100 uM to Less Than 200 nM Screening Hit Early Optimization Sub-uM Affinity ARID1B Kd: 100 uM ARID1B Kd: 15 uM ARID1B Kd: 0.5 uM ARID1B Kd: 0.2 uM 1.4 Å co-xtal 2.0 Å soak 1.9 Å co-xtal 1.7 Å soak structure structure structure
Slide 9: Maximum Optionality Through Parallel Cereblon and VHL Based Degraders
Maximum Optionality Achieved Through Progression of Both Cereblon and VHL Based Degraders in Parallel DC50: 0.35 uM CEREBLON DC50: 3.7 uM VHL 9 | ARID1B-HiBiT HCT116 Colorectal Cell Line
Slide 10: Lead ARID1B Degraders Demonstrate Robust Degradation Across Multiple Cell Lines
Lead ARID1B Degraders Demonstrate Robust Degradation Across Multiple Cell Lines IMMUNOBLOT – HT1376 (Bladder) HiBiT KINETICS – HCT116 (Colorectal) kDa CEREBLON 280 DC50: 0.35 uM ARID1B 116 Vinculin Luminescence Units Units 120 100 Luminescence DC50: 3.7 uM Control) 80 (%(%Control) VHL 60 40 Relative
Slide 11: ARID1B Degradation is On-Mechanism Via Ubiquitin-Proteasome System
ARID1B Degradation is On-Mechanism Via Ubiquitin-Proteasome System Inhibitors of the UPS Pathway VHL-Inactive Degrader Does Not Affect ARID1B Levels Rescue Degradation Degradation Cell Viability Degradation ARID1B degrader + 750 nM MG132 (Proteosome inhibitor) + 250 nM Bortezomib (Velcade, Proteosom
Slide 12: CRBN-Based ARID1B Degrader Does Not Degrade CRBN Neosubstrates
CRBN-Based ARID1B Degrader Does Not Degrade CRBN Neosubstrates GSPT1-HiBiT HEK293T IKZF1-HiBiT Jurkat IKZF3-HiBiT MM1S Degradation Cell Viability | 12
Slide 13: Selective ARID1B Degradation Demonstrated by Global Proteomics
Selective ARID1B Degradation Demonstrated by Global Proteomics VHL-Based Degrader Cereblon-Based Degrader ARID1A ARID1A Log2FC ARID1B degrader 5uM/DMSO 24 hr Log2FC ARID1B degrader 2.5uM/DMSO 24 hr 13 | ARID1B-HiBiT HCT116
Slide 14: Native Mass Spectrometry Demonstrates Ternary Complex Formation
Native Mass Spectrometry Demonstrates Ternary Complex Formation ARID1B Ligase Inactive Active Degrader Pocket Mutant Degrader ARID1B Binary 100% EloB EloC 50% VHL VBC Binary ARID1B Mass Ternary nMS allows for monitoring of binary and ternary complex formation 14 |
Slide 15: First Ternary Complex X-ray Structure Reveals Unexpected Degrader Geometry
First Ternary Complex X-ray Structure Reveals Unexpected Degrader Geometry Paving Way to Improved Degrader Molecules Experimentally determined exit VHL vector ARID1B Hypothesized ARID1B exit vector Determined to 2.31 Å resolution 15 |
Slide 16: First Ternary Complex X-ray Structure Reveals Unexpected Degrader Geometry
First Ternary Complex X-ray Structure Reveals Unexpected Degrader Geometry Paving Way to Improved Degrader Molecules CRBN VHL ARID1B ARID1B Determined to 2.31 Å resolution Determined to 3.17 Å resolution 16 |
Slide 17: Ternary Complex Formation with VHL and CRBN based Degraders
Ternary Complex Formation with VHL and CRBN based Degraders Ternary Complex Formation: TR-FRET & NanoBRET Biochemical Cooperativity: TR-FRET & SPR 1 E3 ligase ARID1B 2 complex 40000 TR-FRET Signal 30000 CRBN binary IC50: 24.5 nM 20000 +ARID1B: 2.7 nM 10000 0 0.1 1 10 100 1000 10000 Compound (nM) 17
Slide 18: FHT-654 modulates ARID1B target gene expression in HCT-116
Relative expression D M S 63 O 12 nM 5 25 n M 0 FHT-654 50 n M 0 10 nM 00 n 63 M ARID1A-/- cells 12 nM 5 25 nM 0 50 nM Protein expression 0 10 nM Ligase Dead 00 nM Relative expression D M S 63 O 12 nM 5 25 nM 0 FHT-654 50 nM 0 10 nM 00 n 63 M 12 nM 5 Gene 48h 25 nM 0 Downregulated 50 n M 0 10 nM 00
Slide 19: Selective SMARCA2 Inhibition: Exploiting Synthetic Lethality with Mutant SMARCA4
Selective SMARCA2 Inhibition: Promising Strategy to Exploit Synthetic Lethal Relationship Between SMARCA2 and Mutant SMARCA4 Healthy Cells Cancer Cells BAF BAF BAF Complex Complex Complex SMARCA2i Mutant SMARCA4 SMARCA2 SMARCA4 SMARCA2 SMARCA4 No SMARCA4 Mutations SMARCA4 Mutation SMARCA4 Mutation a
Slide 20: SMARCA4 Mutations are Consequential in NSCLC
SMARCA4 Mutations are Consequential – in NSCLC, Patients with Mutated SMARCA4 Have Significantly Worse Clinical Outcomes Overall Survival for SMARCA4 wt vs SMARCA4 mut1; SMARCA4 Mutated in Up to 10% of NSCLC Tumors, Frontline Metastatic NSCLC w/ Chemoimmunotherapy Minimal Overlap w/ Other Mutations2
Slide 21: FHD-909 Demonstrated Approximately 33-fold Selectivity Across 17 Cell Lines
FHD-909 Demonstrated Approximately 33-fold Selectivity Across 17 BRG1 Mutant and Wild-Type Cell Lines In Vivo Absolute IC50 (μM) Selectivity = 33x Spread in potency for wild type versus mutant cell lines indicates 33-fold selectivity observed Median IC50 (µM) BRG1 WT 0.0932 BRG1 MUT 0.0028 21 |
Slide 22: FHD-909 in Combination with Anti-PD1 Demonstrates Complete and Durable Regression
FHD-909 in Combination with Anti-PD1 Demonstrates Complete and Durable Regression Double Combo Efficacy (LY4050784, anti-PD1, chemo) MB49 SMARCA4 KO Syngeneic Model % body weight change Body weight percentage change (%) • FHD-909 monotherapy demonstrates better efficacy (tumor regression) than chemo
Slide 23: Lack of Tumor Formation in CR Mice After Re-inoculation Suggests Immune Memory
Lack of Tumor Formation in CR Mice After Re-inoculation Suggests Immune Memory Formation Re-challenge of Mice After CR with FHD-909 + Anti-PD1 Combos Age-matched tumor naïve mice (take rate- 100%) FHD-909 + anti-PD1 CR mice (0%) FHD-909 + Chemo + anti-PD1 CR mice (0% Tumor volume (mm3) (~70 days aft
Slide 24: Thank you!
Acknowledgements Thank you! 24 |