Foghorn Therapeutics Inc. · NASDAQ:FHTX
Foghorn Therapeutics — Investor Presentation (November 2025)
75 slides from Foghorn Therapeutics's investor presentation, Nov 5, 2025
Slide 1: Unique biology, Precision therapeutics, Broad impact
November 2025 Unique biology Precision therapeutics Broad impact NASDAQ LISTED FHTX Exhibit 99.2
Slide 2: Forward Looking Statements
| Forward Looking Statements 2 This presentation contains forward-looking statements that are based on management's beliefs and assumptions and on information currently available to management. All statements other than statements of historical facts contained in this presentation are forward- looki
Slide 3: Foghorn is a Leader in Chromatin Biology, Successfully Drugging Challenging Targets
| Foghorn is a Leader in Chromatin Biology, Successfully Drugging Challenging Targets 3 Targeting chromatin regulation Implicated in up to 50% of all tumors Multi-billion $ Opportunities Unlocking selectivity of previously undruggable targets First-and-Best-in-Class Approaches Innovating selective p
Slide 4: Chromatin Regulatory System Orchestrates Gene Expression
| Chromatin Regulatory System Orchestrates Gene Expression: Multiple Opportunities for Targets and Therapeutics 4 Chromatin – compacted form of DNA inside the nucleus of the cell Chromatin Remodeling Complexes – specialized multiprotein machines that allow access to DNA Targets: SMARCA2, ARID1B Tran
Slide 5: Foghorn's Platform Has Delivered Precision First-in-Class Therapeutics
| Foghorn’s Platform Has Delivered Precision First-in-Class Therapeutics, and is Poised to Unlock New Biology 5 1. Chromatin Biology 2. Chemistry, Biochemistry & Formulations 3. Degraders / Selective Targeting Deep mechanistic understanding of chromatin regulatory system Expertise in rules of degrad
Slide 6: Precision Therapies With Potential for Multi-Billion Dollar Opportunities Across Oncology
| Foghorn: Precision Therapies With Potential for Multi-Billion Dollar Opportunities Across Oncology 6 Modality Program Phase 1 Enzyme Inhibitors Transcription Factor Disruptors Undisclosed Protein Degraders Partner FHD-909* (Selective SMARCA2) 3 Discovery Programs Undisclosed Partnered Undisclosed
Slide 7: Advancing Multiple Programs with Near-Term Milestones
| Advancing Multiple Programs with Near-Term Milestones 7 Phase 1 Monotherapy DataFHD-909* (LY4050784) (Selective SMARCA2 Inhibitor) 2026IND-Ready Selective CBP Degrader 2026IND-enabling StudiesSelective EP300 Degrader ConfidentialTransition to Lilly / INDSelective SMARCA2 Degrader* ConfidentialTran
Slide 8: FHD-909 is Being Developed in Collaboration with Lilly
| FHD-909 is Being Developed in Collaboration with Lilly; Landmark Agreement Signed in December 2021 Significant Upfront and Economics Strong Momentum and Shared Vision Ongoing Discovery Programs • $300 million cash • $80 million in Foghorn common stock at a price of $20 per share • 50/50 U.S. econo
Slide 9: Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer 9 Large Market Potential Chromatin biology is implicated in up to 50% of tumors, potentially impacting ~2.5 million patients Foghorn’s current pipeline potentially addresses more than 500,000 of these patients Broa
Slide 10: Selective SMARCA2 Program For SMARCA4-Mutant Cancers
Selective SMARCA2 Program For SMARCA4-Mutant Cancers • FHD-909 (LY4050784) – Selective SMARCA2 Inhibitor 10
Slide 11: SMARCA2: Clinical-stage FHD-909 Inhibitor and Preclinical Degrader
| SMARCA2: Clinical-stage FHD-909 Selective SMARCA2 Inhibitor and Preclinical Selective SMARCA2 Degrader 11 Selective SMARCA2 Inhibitor FHD-909* Selective SMARCA2 Degrader Biology Exploit the synthetic lethal relationship between SMARCA2 and mutated SMARCA4 Status Phase 1 monotherapy dose escalation
Slide 12: Selective SMARCA2 Inhibition Exploits Synthetic Lethality with Mutant SMARCA4
| Selective SMARCA2 Inhibition: Promising Strategy to Exploit Synthetic Lethal Relationship Between SMARCA2 and Mutant SMARCA4 12 No SMARCA4 Mutations SMARCA4 Mutation SMARCA4 Mutation and SMARCA2i Cell Survival Cell Death Healthy Cells Cancer Cells SMARCA4 SMARCA2 BAF Complex BAF Complex Mutant SMA
Slide 13: SMARCA4 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors
| SMARCA4 is Mutated in Up to 10% of NSCLC; Up to 5% of Solid Tumors 13 SMARCA4 mutated across a broad range of tumors Accounts for ~5% of solid tumors AACR GENIE via cBioPortal
Slide 14: SMARCA4 Mutations are Consequential in NSCLC
| NSCLC patients with SMARCA4 mutations: ─ Poor prognosis ─ Shorter overall survival ─ Less responsive to immune checkpoint inhibitors ─ Clinically definable, high unmet need population SMARCA4 Mutated in Up to 10% of NSCLC Tumors, Minimal Overlap With Other Mutations2Overall Survival for SMARCA4wt
Slide 15: SMARCA4 and KRAS Co-Mutations Have Even Worse Outcomes
| When SMARCA4 and KRAS Mutations Co-Occur, Patients Have Even Worse Outcomes to Standard of Care Treatment In response to PD(L)-1 therapy, Patients with Co-Occurring SMARCA4 and KRAS Mutations have a Shorter ORR, PFS, and OS than Patients with only KRASmut 15 Overall Response Rate (ORR) Source: Ale
Slide 16: FHD-909: Goal is First-Line Treatment for SMARCA4-Mutated NSCLC
| FHD-909: Overall Goal is to Become a First-Line Treatment for SMARCA4-Mutated NSCLC 16 1st Line NSCLC Pembrolizumab-based regimens Other immune checkpoint inhibitor-based regimens Chemotherapy-based regimens 2nd Line NSCLC Chemotherapy-based regimens Ramucirumab (anti-VEGF) + chemotherapy Checkpoi
Slide 17: FHD-909 Positioned to Be Evaluated in Combination with Standard Therapies
| Chemotherapy Targeted Therapies FHD-909 is Positioned to Be Evaluated in Combination with Standard Therapies FHD-909 shows significant anti-tumor activity preclinically in combination with standard therapies in NSCLC 17 Cisplatin PemetrexedPaclitaxel KRAS inhibitorsPembrolizumab
Slide 18: First-in-Human Phase 1 Trial of FHD-909
| A First-in-Human Phase 1 Trial of FHD-909 in Advanced Solid Tumor Patients with SMARCA4 Mutations Phase 1a Dose Escalation Advanced solid tumors with any SMARCA4 alteration (mTPI-2 method with backfillinga) Dose Level 1 Dose Level 2 Dose Level 3 Dose Level n Phase 1b Dose Expansionb Presence of a
Slide 19: Degrader Programs
Degrader Programs • Selective CBP Degrader • Selective EP300 Degrader • Selective ARID1B Degrader 19
Slide 20: Developing a Portfolio of Novel and Selective Degraders
| Developing a Portfolio of Novel and Selective Degraders 20 Selective ARID1B Degrader Selective CBP Degrader • Mutated in up to 5% of all solid tumors • First to demonstrate robust and selective degradation of the protein • Developing VHL and cereblon degraders, potential for oral delivery • Progra
Slide 21: CBP and EP300 Proteins – A Decades Long Challenge in Selectivity
| CBP and EP300 Proteins – A Decades Long Challenge in Selectivity 21 CBP and EP300 Biology • CBP and EP300 are highly homologous, paralog histone acetyltransferases regulating enhancer-mediated transcription and protein stability • Dysregulation of CBP and EP300 has been implicated in multiple canc
Slide 22: Selective CBP Degrader
Selective CBP Degrader For EP300-Mutant and CBP-Dependent Cancers 22
Slide 23: Summary: Selective CBP Degrader
| Summary: Selective CBP Degrader for EP300-Mutant & CBP-Dependent Cancers 23 * Per year incidence in the U.S., EU5, Japan . Source: Clarivate DRG Mature Markets Data. • CREB binding protein (CBP) • Targeted protein degrader Target / Approach • Preclinical • IND-ready in 2026 Stage / Next Milestone
Slide 24: Selective CBP Degradation Shows Anti-Tumor Activity in EP300mut Models
| Selective CBP Degradation Results in Significant Anti-Tumor Activity in EP300mut Solid Tumor Models 24 EP300mut Bladder Cancer CDX (639V) EP300mut Gastric Cancer CDX (AGS) EP300mut Gastric Cancer PDX (ST020326) T u m o r V o lu m e (m m ³ + S E M ) B o d y W ei g h t C h an g e (% ) 20 30 40 50 60
Slide 25: Selective CBP Degradation Spared Platelets and Megakaryocytes
| Selective CBP Degradation Showed No Significant Impact on Platelet Counts and Spared Megakaryocytes 25 Platelet Counts Post Two Weeks of Dosing (In Vivo – Control Mice) Human Megakaryocyte Cell Viability Assay (In Vitro*) dCBP-59 CCS1477 (Inobrodib) Vehicle dCBP-59 (10 mg/kg, QD, SC) Vehicle CCS14
Slide 26: CBP Degradation Disrupts ER Signaling in Breast Cancer
| In Breast Cancer, CBP Degradation Disrupts Estrogen Receptor (ER) Signaling and Inhibits Tumor Cell Growth CBP Robust & Potent CBP degradation …Resulting in cancer cell growth inhibition 26 0. 00 01 0. 00 1 0. 01 0. 1 1 10 10 0 10 00 10 00 0 10 00 00 10 00 00 0 % d e te c te d C B P p ro te in CBP
Slide 27: CBP Degrader Shows Promise in Combination in ER+ Breast Cancer Models
| Foghorn Selective CBP Degrader Shows Promise in Combination with Standard Therapies in Preclinical ER+ Breast Cancer Models 27 CDK4/6 Inhibitor + Fulvestrant CBP Degrader (FHT-CBPd-41) + CDK4/6 inhibitor + Fulvestrant Cancer cell growth only significantly inhibited at highest concentrations of SoC
Slide 28: CBPd-171 is Highly Selective
| Foghorn’s Pre-DC CBP Degrader (CBPd-171) is Highly Selective 28 CBPd-171 rapidly and potently degrades CBP, but not its paralog EP300 Dmax (%): 97% | Max Rate: 3.2 | DC50: 30pM Dmax (%): 5% | Max Rate: N/A F ra c ti o n a l L u m in e s c en ce (R L U ) 0 5 10 15 20 25 0.0 0.2 0.4 0.6 0.8 1.0 1.2
Slide 29: CBPd-171 is Highly Selective by Global Proteomics
| Foghorn’s Pre-DC CBP Degrader (CBPd-171) is Highly Selective by Global Proteomics 29 U2OS CBPd-171/DMSO 100 nM 3hr Log2FC
Slide 30: Long-Acting Injectable Formulation of CBPd-171
| Long-Acting Injectable Formulation of CBPd-171 Enables Weekly Sub-Cutaneous (SC) Delivery 30 Tumor Growth Inhibition Observed in EP300mut (AGS) Gastric Model (Daily Injections and SC weekly LAI Injection) • Weekly LAI injection of CBDd-171 results in efficacy comparable to daily SC injections in A
Slide 31: Selective EP300 Degrader
Selective EP300 Degrader For CBP-Mutant and EP300-Dependent Cancers 31
Slide 32: Summary: Selective EP300 Degrader
| Summary: Selective EP300 Degrader for CBP-Mutant & EP300-Dependent Cancers 32 * Per year incidence in the U.S., EU5, Japan. Source: Clarivate DRG Mature Markets Data. • E1A binding protein p300 (EP300) • Targeted protein degrader Target / Approach • Broad range of heme malignancies focused on Mult
Slide 33: Selective EP300 Degraders are Highly Potent and Selective
| Foghorn’s Selective EP300 Degraders (EP300d) are Highly Potent and Selective 33 Dmax (%): 95% | Max Rate: 2.5 | DC50: 3nM Dmax (%): 5% | Max Rate: N/A EP300 Cellular Kinetics CBP Cellular Kinetics EP300d-31 rapidly and potently degrades EP300, but not its paralog CBP
Slide 34: EP300d-79 is Highly Selective by Global Proteomics
| Foghorn’s EP300 Degrader (EP300d-79) is Highly Selective by Global Proteomics 34 U2OS EP300d/DMSO 300 nM 6hr Log2FC
Slide 35: EP300 Degradation Shows Activity in Hematological Malignancies
| EP300 Degradation Shows Anti-Proliferative Activity in Broad Range of Hematological Malignancies 35MM: Multiple Myeloma; DLBCL: Diffuse Large B-Cell Lymphoma; AML: Acute Myeloid Leukemia; BL: Burkitt’s Lymphoma; TCL: T-cell Lymphomas; T-ALL: T-cell Acute Lymphoblastic Leukemia; B-ALL: B-cell Acute
Slide 36: EP300 Degradation Inhibits Tumor Growth in Myeloma, DLBCL and Prostate Models
| Multiple Myeloma (MM1S) CDX DLBCL (KARPAS422) CDX AR+ Prostate (VCaP) CDX EP300 Degradation Results in Significant Tumor Growth Inhibition in Multiple Myeloma, DLBCL and Prostate Models 36 B o d y W ei g h t C h an g e ( % ) 5 10 15 20 25 30 35 40 45 0 500 1,000 1,500 2,000 Vehicle FHT-EP300d - 32
Slide 37: EP300 Degradation Modulates Transcription Factors in Multiple Myeloma
| EP300 Degradation Modulates the Transcription Factors That Multiple Myeloma Depends On 37 EP300 degradation downregulates the expression of several transcription factors H929 OPM2 Lineage-dependence on EP300-regulated transcription factors KMS11RPMI8226 OPM2 RPMI8226 KMS11 dEP300-9 treatment, cell
Slide 38: Selective EP300 Degradation Induces Apoptosis in MM
| Selective EP300 Degradation Induces Apoptosis in MM 38 Treatment with a selective EP300 degrader (dEP300-079) results in time- and concentration- dependent induction of apoptosis MM1S cell line
Slide 39: Selective EP300 Degradation Gives Responses In Vivo and Spares Platelets
| Selective EP300 Degradation Results in Significant Responses In Vivo, and Spares Platelets 39 • The max efficacious dose for inobrodib results in stasis with daily dosing. However, inobrodib use in the clinic is limited by thrombocytopenia, which requires dosing holidays • Selective EP300 degrader
Slide 40: VHL-Based EP300 Degrader Maintains Activity in IMiD Resistant Cell Lines
| VHL-Based Selective EP300 Degrader Maintains Activity in IMiD Resistant Cell Lines 40 Resistant MM1S cell lines were developed through 5–6 months of in vitro exposure to gradually increasing concentrations of lenalidomide, pomalidomide, iberdomide, or mezigdomide dEP300-9 dEP300-9 pomalidomide len
Slide 41: Synergy Demonstrated Between dEP300 and Pomalidomide
| Synergy Demonstrated in MM Between dEP300 and Pomalidomide 41 Extensive combination screen assessed the impact on growth following treatment with dEP300 and 33 approved agents across 6 different cell lines
Slide 42: Selective EP300 Degraders Approaching Pre-DC CBA
| Selective EP300 Degraders Approaching Pre-DC CBACompound 0.3 [104%]0.3 [99%]0.4 [95%]U2OS EP300 uDC50 (nM) [Dmax%] On- Target <0.15Actioned2.1MM1S EP300 uDC90 (24 hr, nM) 0.152.00.61MM1S (nM, uGI50) 31 / >10,000102 / >10,0004 / 3000CBP / BRD4 TR-FRET IC50 (nM) Off-Target 356x [63%]17497x [--]26x [
Slide 43: Selective ARID1B Degrader For ARID1A-Mutant Cancers
Selective ARID1B Degrader For ARID1A-Mutant Cancers 43
Slide 44: ARID1B is a Major Synthetic Lethal Target
| ARID1B is a Major Synthetic Lethal Target with Potential in Up To 5% of All Solid Tumors 44 * Per year incidence in the U.S., EU5, Japan. Source: Clarivate DRG Mature Markets Data. • ARID1B • Targeted protein degrader Target / Approach • Preclinical • In vivo proof of concept in 2026 Stage / Next
Slide 45: ARID1B: Drugging A Previously Undruggable Target
| ARID1B: Drugging A Previously Undruggable Target • Large and highly unstructured protein ~ 240 kDa • No known enzymatic function • Member of large, multi-subunit complex • High sequence homology (~60%) to ARID1A 45 ARID1A/B BAF Nucleosome PDB ID: 6LTJ • Discover binders to ARID1B • Use binders to
Slide 46: Platform Yields Several Selective ARID1B Binder Series
| Foghorn Platform Yields Several Selective ARID1B Binder Series 46 ARID1B ARID1A KD= 25.3 ± 3.4 µM N= 0.90 ± 0.02 ARID1B ARID1A >2x selectivity for ARID1B ARID1B Binding A R ID 1A B in di ng SERIES A SERIES B
Slide 47: Cereblon and VHL Based Degraders Progressed in Parallel
| Maximum Optionality Achieved Through Progression of Both Cereblon and VHL Based Degraders in Parallel 47 C E R E B L O N V H L
Slide 48: Lead ARID1B Degrader Shows Robust Degradation Across Cell Lines
| Lead ARID1B Degrader Demonstrates Robust Degradation Across Multiple Cell Lines 48 IMMUNOBLOT HiBiT - ENDPOINT HCT116 (Colorectal)HT-1376 (Bladder) HiBiT – KINETICS HCT116 (Colorectal) 24 hours 24 hours R e la ti v e L u m in es c e n c e U n it s (% C o n tr o l)
Slide 49: ARID1B Degradation is On-Mechanism Via Ubiquitin-Proteasome System
| ARID1B Degradation is On-Mechanism Via Ubiquitin-Proteasome System 49 Inhibitors of the UPS Pathway Rescue Degradation VHL-Inactive Degrader Does Not Affect ARID1B Levels Degradation Cell Viability Degradation + 750 nM MG132 (Proteosome inhibitor) + 250 nM Bortezomib (Velcade, Proteosome inhibitor
Slide 50: ARID1B Degrader Exhibits High Target Selectivity
| ARID1B Degrader Exhibits High Target Selectivity 50 ARID1B-HiBiT HCT116 ARID1A-HiBiT HCT116 SMARCA2-HiBiT HeLa SMARCA4-HiBiT HeLa
Slide 51: Selective ARID1B Degradation Demonstrated by Global Proteomics
| Selective ARID1B Degradation Demonstrated by Global Proteomics 51
Slide 52: ARID1B Degradation Affects Downstream Target Genes
| 0.0 0.2 0.4 0.6 0.8 1.0 1 2 3 4 5 6 Selective ARID1B Degradation has Demonstrated Effects on Downstream Target Genes – Progressing Towards Proof of Concept 52 3 Day ARID1B shRNA Treatment ARID1B Degrader Treatment y = 0.6782x + 0.2591 R² = 0.7754 0.00 0.20 0.40 0.60 0.80 1.00 1.20 0.0 0.5 1.0 ARID
Slide 53: Advancing Multiple Programs with Near-Term Milestones
| Advancing Multiple Programs with Near-Term Milestones 53 Phase 1 Monotherapy DataFHD-909* (LY4050784) (Selective SMARCA2 Inhibitor) 2026IND Ready Selective CBP Degrader 2026Development CandidateSelective EP300 Degrader ConfidentialTransition to Lilly / INDSelective SMARCA2 Degrader* ConfidentialTr
Slide 54: Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer
| Developing First-in-Class Precision Medicines Targeting Major Unmet Needs in Cancer 54 Large Market Potential Chromatin biology is implicated in up to 50% of tumors, potentially impacting ~2.5 million patients Foghorn’s current pipeline potentially addresses more than 500,000 of these patients Bro
Slide 55: Unique biology, Precision therapeutics, Broad impact
Unique biology Precision therapeutics Broad impact 55 November 2025
Slide 56: Appendix
Appendix 56
Slide 57: SMARCA2 Program
SMARCA2 Program FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex 57
Slide 58: FHD-909 is Highly Selective for SMARCA2 Over SMARCA4
| FHD-909 is Highly Selective for SMARCA2 Over SMARCA4 58 FHD-909 Demonstrated Approximately 33-fold Selectivity Across SMARCA4 Mutant and Wild-Type Cell Lines In Vitro Selectivity = 33x Median IC50 (µM) 0.0932SMARCA4 WT 0.0028SMARCA4 MUT NCI-H460, Lung model (NSCLC / SMARCA4-wildtype) FHD-909 is hi
Slide 59: FHD-909 Monotherapy Regression in NCI-H2126 NSCLC Model
| FHD-909 Monotherapy Demonstrated Regression In Vivo in NCI-H2126 SMARCA4 Mutant NSCLC Model at Tolerated Doses 59 NCI-H2126 Reduction in Tumor Volume NCI-H2126 Body Weight Genetic Background: SMARCA4 W764R, TP53 E62*, STK11-/-, CDKN2A-/-, KEAP1 R272C NOTE: All doses were well tolerated. Dosing hol
Slide 60: FHD-909 Strong In Vivo Activity Across SMARCA4 Mutant NSCLC Models
| FHD-909 Monotherapy Demonstrated Strong In Vivo Activity Across SMARCA4 Mutant NSCLC Models at Tolerated Doses 60 0 7 14 21 28 100 200 300 400 500 Days of Dosing (Dose Start Day1) Vehicle Control FHD-909, 20mg/kg, BID, PO FHD-909, 40mg/kg, BID, PO FHD-909, 60mg/kg, BID, PO A549 Model RERF-LC-AI Mo
Slide 61: FHD-909 with Standard Therapies in A549 Xenograft Model
| FHD-909 in Combination with Standard Therapies Demonstrates Significant Activity in the A549 (SMARCA4 mutant, KRAS G12S) Xenograft NSCLC Model 61 0 7 14 21 28 200 400 600 800 1000 1200 Days of Dosing (Dose Start Day 1) T u m o r vo lu m e (m m 3 ) * * * * ** ## Note: * p≤0.05 for pairwise comparis
Slide 62: FHD-909 with Standard Therapies in RERF-LC-AI Xenograft Model
| FHD-909 in Combination with Standard Therapies Demonstrates Significant Activity in the RERF-LC-AI (SMARCA4 mutant) Xenograft NSCLC Model 62 0 7 14 21 28 200 400 600 800 1000 1200 1400 Days of Dosing (Dose Start Day 1) T u m o r V o lu m e (m m 3 ) * * * * **# # Note: * p≤0.05 for pairwise compari
Slide 63: Synergy of FHD-909 with KRAS Inhibitors In Vitro
| Synergistic Activity Observed for FHD-909 in Combination with KRAS Inhibitors In Vitro 63 In h ib it io n ( % ) In h ib it io n ( % ) FHD-909 + olomorasib (KRAS G12C inhibitor) FHD-909 + pan-KRAS inhibitor In h ib it io n ( % ) In h ib it io n ( % ) 1 10 100 1000 10000 -20 0 20 40 60 80 100 120 FH
Slide 64: FHD-909 with KRAS Inhibitors in NSCLC Xenograft Models (Olomorasib)
| Combination of FHD-909 with KRAS Inhibitors Demonstrates Synergistic Activity in SMARCA4, KRAS Co-Mutated Human NSCLC Xenograft Models In Vivo FHD-909 + olomorasib (KRAS G12C inh) NCI-H2030 (SMARCA4mt, KRAS G12C) 64 0 7 14 21 28 0 500 1000 1500 2000 2500 3000 Days of Dosing (Dose Start Day1) T u m
Slide 65: FHD-909 with KRAS Inhibitors in NSCLC Xenograft Models (Pan-KRAS)
| Combination of FHD-909 with KRAS Inhibitors Demonstrates Synergistic Activity in SMARCA4, KRAS Co-Mutated Human NSCLC Xenograft Models In Vivo FHD-909 + pan-KRAS inh A549 (SMARCA4mt, KRAS G12S) 65 Combination of FHD-909 with pan-KRAS inhibitor resulted in synergistic antitumor activity and sustain
Slide 66: FHD-909 with Pembrolizumab in Humanized Xenograft NSCLC Model
| FHD-909 in Combination with Pembrolizumab Shows Significantly Enhanced Anti-Tumor Activity in A549 CD34+ HSC Humanized Xenograft NSCLC Model 66 FHD-909 sensitized the tumor cells to pembrolizumab treatment resulting in enhanced combination activity. Pembrolizumab alone had no effect on tumor growt
Slide 67: Selective SMARCA2 Degrader Achieved Complete Degradation In Vitro
| Selective SMARCA2 Degrader Achieved Complete SMARCA2 Degradation and Cell Growth Inhibition In Vitro 67 Degraders Caused Time- and Dose-Dependent SMARCA2 Degradation Antiproliferative Effects in A549 Mutant NSCLC Model A549 Ten-Day Proliferation AssaySMARCA2 / SMARCA4 HIBIT Data SMARCA2 SMARCA4 %
Slide 68: Induced Proximity Platform Evolution
Induced Proximity Platform Evolution FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex 68
Slide 69: Existing Capabilities Setting Foundation for Expansion Into Induced Proximity
| Existing Capabilities Have Produced Multiple Degrader Programs and are Setting Foundation for Expansion Into Induced Proximity 69 TargetDegrader Machinery (E3 Ligase) TargetEffector Post-Translational modification - dependent Protein Stabilization Modulation of gene activation/repression Induced P
Slide 70: Induced Proximity Platform Demonstrates Initial POC for DUBTAC
| Induced Proximity Platform Demonstrates Initial POC for DUBTAC 70 increase in protein levels DUBTACs (deubiquitinase targeting chimera) are heterobifunctional molecules that recruit a DUB to a target of interest in order to remove the ubiquitin “degradation tag”, thereby resulting in protein stabi
Slide 71: Induced Proximity Potential to Activate Cell Death Cascade
| Induced Proximity Platform Demonstrates Potential for Novel Approach to Activate Cell Death Cascade 71 Normal BCL6 Function BCL6 Activation with BAF-BCL6 Heterobifunctional • BCL6 is a proto-oncogene, which binds to promoters of cell death genes and suppresses their expression • We have developed
Slide 72: Induced Proximity Offers Expansion Beyond Oncology; Nuclear Hormone Receptors
| 48 Nuclear Hormone Receptors Nuclear hormone receptor are implicated in multiple biology processes across most organ systems • Only 10 nuclear hormone receptors have been drugged and approved to date (e.g., AR, ER Glucocorticoids, thyroid HR alpha beta) • Despite decades of development most others
Slide 73: Degrader Platform Uniquely Enables Expansion into Induced Proximity
| Degrader Design Degrader Optimization Degrader Development Best-in-Class Induced Proximity Modulator • Structural prediction/ docking • Well-developed toolkit • Flexibility- rigidity • Charge • Hydrophobicity • Commercial and proprietary covalent and fragment screening libraries • Target binders •
Slide 74: Drugging Transcription Factors Multiple Approaches
Drugging Transcription Factors Multiple Approaches FHD-609 is a Selective, Potent, Protein Degrader of the BRD9 component of the BAF complex 74
Slide 75: Foghorn's Transcription Factor Platform: Approaches
| Foghorn’s Transcription Factor Platform: 4 Approaches 75 Transcription Factor Chromatin Remodeler Modulating TF activity via Protein-Protein Interaction Disruptors Transcription Factor Native E3 Ligase Degrading TFs via recruitment of the native E3 ligase using molecular glue = MG (Molecular Glue)
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