camibirstat (FHD-286) / Foghorn Therap, Montefiore Medical Center - LARVOL DELTA

mSWI/SNF Complex Inhibition Sensitizes KRAS-Mutant Lung Cancers to Targeted Therapies via Epithelial-Mesenchymal Subversion (IASLC-WCLC 2026) - "Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-sensitive and -resistant PDO models and in vivo PDX systems. Conclusions : These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, potentiate duration of response, and mitigate emergence of resistance."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • SMARCA4

Notable Efficacy of Co-Treatment with FHD-286, a Dual BRG1/BRM ATP-Ase Inhibitor, and Menin or BET Inhibitor, Decitabine or Venetoclax Against AML with MLL-r or Mutant NPM1 (ASH 2023) - "BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPase within the multi-protein, ATP-dependent, chromatin remodeling BAF complexes that regulate gene transcription. Finally, co-treatment with FHD-286 and OTX015 or SNDX-5613 (oral gavage) was significantly more effective than each drug alone in reducing the AML burden and overall survival of mice engrafted with a separate PDX model of AML cells with mtNPM1 and FLT3-ITD, without significant toxicity. These findings demonstrate the pre-clinical efficacy of FHD-286-based rational combinations and underscore their promise against AML with MLL1r or mtNPM1."

Clinical • IO biomarker • Acute Myelogenous Leukemia • BCL2 • BRD4 • CASP3 • CD123 • CD33 • CD99 • CDK4 • CDKN1A • CEBPA • CLEC12A • FLT3 • HEXIM1 • IL3RA • ITGAM • MCL1 • MEF2C • MYC • NPM1 • PBX3 • PLK1 • SMARCA2 • SMARCA4

A phase I dose escalation and expansion study of FHD-286, a novel BRG1/BRM (SMARCA4/SMARCA2) inhibitor, for the treatment of metastatic uveal melanoma (ESMO 2023) - P1 | "The RP2D(s) has not yet been established. Updated dosing, safety, tolerability, PK and anti-tumor activity data will be shared at the meeting."

Metastases • P1 data • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • SMARCA2 • SMARCA4

Superior Preclinical Efficacy of BRG1/BRM Inhibitor Combined With BET Inhibitor or Decitabine Against MECOM-rearranged (MECOM-r) Acute Myeloid Leukemia (AML) (SOHO 2025) - "Taken together, these findings highlight the promise of FHD-286– based rational combinations, especially with BETi, navitoclax, or decitabine, in exerting significant anti-AML efficacy against cellular models of MECOM-r AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD93 • CDK4 • GATA2 • ITGAM • KIT • MECOM • MYC • PLK1 • SMARCA4

PRC2 loss in MPNST is accompanied by SWI/SNF complex rewiring and sensitization to SMARCA2/4 and BET inhibition in vivo. (PubMed, Mol Cell Proteomics) - "Finally, evaluating the efficacy of FHD-286 alone, and in combination with I-BET-762, in an isogenic PRC2 loss murine allograft MPNST model, we observed enhanced efficacy of the combination regimen compared to either single agent in the Suz12 KO arm, while in the Suz12 WT arm, the combo was outperformed by I-BET-762 alone. Together, our findings indicate that PRC2 loss in MPNST is accompanied by selective subunit remodeling and genomic redistribution of SWI/SNF complexes and support SWI/SNF ATPase inhibition, alone and in combination with BET inhibition, as an attractive therapeutic strategy for PRC2-deficient MPNSTs."

Journal • Preclinical • Brain Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • NF1 • SMARCA2 • SMARCA4 • SMARCD3 • SUZ12

A Phase 1 Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients With Advanced Myeloid Malignancies. (PubMed, Clin Cancer Res) - P1 | "DS was the most frequent serious TRAE. While antileukemic activity was observed, no objective responses were achieved and disease progression frequently occurred within 1-2 treatment cycles. Blast reductions were reported across cytogenetic and mutational profiles, coupled with myeloid differentiation via BRG1/BRM inhibition. This novel mechanism warrants further investigation of FHD-286 in combination with other agents in myeloid malignancies."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Hepatology • Leukemia • Myelodysplastic Syndrome • Oncology • Xerostomia • SMARCA2 • SMARCA4

Novel combination therapies to overcome non-genetic/adaptive menin inhibitor resistance in AML with MLL1r or mtNPM1 (AACR 2024) - "In vivo treatment with FHD-286 and OTX015 or SNDX-5613 significantly reduced the AML burden in mice bearing OCI-AML3-MITR xenografts. These findings underscore preclinical activity of epigenetically-targeted agent-based combinations and highlight their promise in overcoming MI resistance in AML with MLL1r or mtNPM1."

Combination therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BRD4 • CDK6 • CLEC12A • CREBBP • EP300 • FLT3 • HOXA9 • IGF2BP2 • MEF2C • MEIS1 • NPM1 • PBX3 • SMARCA2 • SMARCA4

Identifying ’Druggable’ Targets and Preclinically Overcoming Non-Genetic/Adaptive Resistance to Menin Inhibitors in AML with MLL1r or mtNPM1 (ASH 2024) - "These MITR cells exhibited cross-resistance to other MIs, including ziftomenib and DS1594b...Notably, in a luciferized MLL1r MITR AML PDX model, compared to treatment with each agent alone, co-treatment with FHD-286 and SNDX-5613 or OTX015 for 8-weeks yielded significantly superior survival of the NSG mice (p < 0.05). These findings demonstrate that co-treatment with FHD-286 overcomes in vitro and in vivo MI-resistance, while significantly improving in vivo efficacy of BETi in the cell-line xenograft and PDX models of MITR AML cells. They also show that combinations of epigenetically targeted agents may be effective in MI-sensitive or -resistant AML with MLL1r or mtNPM1."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BRD4 • CDK6 • CLEC12A • CREBBP • EP300 • FLT3 • HOXA9 • IGF2BP2 • MEF2C • MEIS1 • NPM1 • PBX3 • SMARCA4

Superior preclinical efficacy of BRG1/BRM inhibitor combined with BET inhibitor or decitabine against MECOM-rearranged AML (AACR 2025) - "Finally, as compared to treatment with each drug alone or vehicle control, in PD xenograft (PDX) models of AML cells with MECOM-r, co-treatment with FHD-286 and decitabine or OTX015 significantly reduced AML burden and improved overall survival of the NSG mice, without inducing significant toxicity. Taken together, these findings highlight the promise of FHD-286 treatment alone and in rational combinations in exerting significant anti-AML efficacy against cellular models of AML, especially those with MECOM-r and EVI1 overexpression."

Preclinical • Acute Myelogenous Leukemia • Oncology • CD93 • CDK4 • GATA2 • ITGAM • KIT • MECOM • MYC • PLK1 • SMARCA2 • SMARCA4

mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion. (PubMed, bioRxiv) - "Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • SMARCA4

Neuroblastoma phenotypic switching is blocked by FHD-286, a small molecule inhibitor of the SWI/SNF ATPases SMARCA2/4 (AACR 2026) - "An evaluation of the combination of FHD-286 and etoposide in an in vivo PDX model is ongoing. Together, these findings establish FHD-286 as a novel therapeutic strategy for targeting chemoresistance and inhibiting NB plasticity and phenotypic switching and, when combined with cytotoxic agents, may be a promising agent for improving treatment outcomes for NB patients."

Late-breaking abstract • Neuroblastoma • Oncology • Solid Tumor • SMARCA2 • SMARCA4

Reprogramming anti-tumor immunity through therapeutic antagonism of the mSWI SNF chromatin remodeling complex (AACR 2026) - "Here, we leveraged two recently developed, selective, orally bioavailable SWI/SNF ATPase antagonists, the PROTAC-based degrader AU-24118 and the catalytic ATPase inhibitor FHD-286, to enable systemic mSWI/SNF antagonism and allow comprehensive interrogation of mSWI/SNF function across tumor, myeloid, and lymphoid compartments under physiologically relevant conditions...Mechanistically, integrative ATAC-seq, ChIP-seq, and RNA-seq analyses demonstrated that SWI/SNF antagonism induces a global collapse of chromatin accessibility in immunosuppressive populations at regulatory elements occupied by lineage-defining transcription factors thereby extinguishing transcriptional programs that sustain immunosuppression. Collectively, these findings identify a targetable epigenetic dependency in immunosuppressive populations within the tumor microenvironment and establish mSWI/SNF antagonism as a precision strategy to overcome immunosuppressive TME-driven resistance to cancer..."

Late-breaking abstract • Oncology • SMARCA2

SMARCA4/2 Inhibitor for POU2F3-Positive SCLC (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: Dana-Farber Cancer Institute

New P2 trial • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • POU2F3

Synergistic targeting of mSWI/SNF and UTX reveals a novel combination therapy in T-cell acute lymphoblastic leukemia (AACR 2026) - "Transcriptomic analyses indicated that genes promoting ribosomal and mitochondrial function were substantially downregulated in UTX KO T-ALL cells treated with FHD-286 but not in similarly treated WT cells, suggesting a previously unrecognized role of UTX in gene regulation. Overall, these findings demonstrate that simultaneously targeting the mSWI/SNF complex and UTX may represent an innovative combinatorial strategy for T-ALL treatment."

Combination therapy • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • NOTCH1 • RUNX1 • SMARCA2

Shifted mSWI/SNF complex assembly and function underlie therapeutically targetable dependencies in endometrial carcinoma (AACR 2024) - "Further, FHD-286 synergized with carboplatin, leading to significant reduction in tumor burden in ARID1A- and ARID1A/B-mutant PDX models. Taken together, these findings reveal the oncogenic contributions of shifted of mSWI/SNF family complex abundance and chromatin-level gene regulatory function and suggest therapeutic utility of mSWI/SNF complex small molecule inhibitors in endometrial carcinoma and other cBAF-disrupted cancer types."

Endometrial Cancer • Oncology • Solid Tumor • ARID1A • ARID1B • ER • SMARCA4

MYC-mediated resistance to immune activation by SWI/SNF mutation or chemical inhibition (AACR 2025) - "SWI/SNF ATPase inhibitors (FHD-286, BRD98, and BRM014) and degraders (ACBI1) similarly induce ISGs through a cGAS/STING-dependent mechanism...This study highlights the suppressive effect of MYC overexpression on IFN-I responses in ARID1A-deficient cancers and suggests a potential link to therapeutic resistance in MYC-high tumors. While the precise molecular mechanisms remain to be fully elucidated, these findings provide a foundation for future studies aimed at understanding the interplay between oncogenic drivers and immune signaling pathways, with implications for developing more effective therapeutic strategies."

Oncology • ARID1A • CD8 • CTNNB1 • KRAS • MYC • STING

FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=33 | Recruiting | Sponsor: Montefiore Medical Center | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Overcoming Menin inhibitor resistance in AML cells with combinations including BET proteins and dual BRG1/BRM inhibitor. (PubMed, Blood) - "Compared to each drug alone, co-treatment with SNDX-5613 (revumenib) and FHD-286 or OTX015 and FHD-286 significantly reduced the in vivo AML burden and improved survival of the immune depleted mice, without inducing significant toxicity, in the xenograft models of MITR and MI-resistant PD MLL1-r AML cells. These findings highlight novel, targeted, drug combinations that overcome MI resistance in AML cells with MLL1-r or mtNPM1."

Journal • Acute Myelogenous Leukemia • BRD4 • CREBBP • HOXA9 • MEIS1 • NPM1 • SMARCA2 • SMARCA4

Yatiri Bio Accurately Predicts AML Drug Response in Blinded Study Using Foghorn’s FHD-286 (GlobeNewswire) - "Yatiri Bio correctly identified patients who achieved complete or partial responses (CR/PR) and accurately classified patients who experienced stable disease or treatment failure. All predictions were generated exclusively from pre-dose peripheral blood samples, without access to additional patient information, including mutational status, dosing, trial arm assignment, or clinical outcomes....As a result of this work, Yatiri Bio and Foghorn Therapeutics have now signed a collaboration agreement for Foghorn to supply material for the further clinical development of FHD-286....The terms of the agreement include clinical, and sales milestones valued at >$40M."

Licensing / partnership • P1 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Distinct 3D chromatin organisation underlies neuroendocrine plasticity in prostate cancer (LCC 2026) - "Furthermore, pharmacological inhibition of chromatin remodelling using the SWI/SNF inhibitor FHD-286 disrupted NE-associated gene expression and suppressed cell proliferation in vitro. Taken together, our findings establish 3D chromatin remodelling as a key driver of luminal-to-neuroendocrine plasticity in prostate cancer and highlight promising therapeutic strategies to mitigate the NEPC state."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FOXA1 • FOXA2 • HOXB13

Highly effective combination of BRG1/BRM inhibitor with BET inhibitor or decitabine for high-risk MECOM-rearranged AML. (PubMed, Hemasphere) - "In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression."

Journal • Acute Myelogenous Leukemia • CDK4 • GATA2 • MECOM • MYC • SMARCA2 • SMARCA4

FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=33 | Not yet recruiting | Sponsor: Montefiore Medical Center

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Machine learning-powered integration of global proteomics and ex vivo sensitivity unveils a protein signature predictive of treatment success to AML therapy: Validation in patients treated with FHD-286, a SMARCA2/4 dual inhibitor (ASH 2025) - P1 | "Patients had received a median 3 prior lines of therapy (range 1-7),including venetoclax and hypomethylating agents (100%), high-dose chemotherapy (71%), and stem celltransplant (57%). A clinical trial prospectively assigning patients tospecific treatment arms based on our proteomics signature will launch in 2025. This result highlights theutility of Yatiri Bio's deep learning model to guide AML treatment decisions and improve outcomes andsupports the development of a mass spectrometry-based clinical assay for patient selection in clinicaltrials."

Machine learning • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • SMARCA2 • TP53

BRM/BRG1 is a novel therapeutic target in ZNF384-rearranged mixed phenotype acute leukemia (ASH 2025) - "At the chromatin level, FHD-286 not only results in loss of BRG1 binding but also,interestingly, in loss of ZNF384 binding, suggesting that inhibiton of BRM/BRG1 may specifically affect theZNF384 fusion protein. We have established cell line-derived and patient-derived xenograft models ofZNF384-r MPAL and will confirm our findings in vivo in pre-clinical studies."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • CCNB1 • CDK1 • CDK6 • EP300 • SMARCA4 • ZNF384

Genomic and phenotypic impact of FHD-286–induced inhibition of SMARCA4/2 in patients with relapsed/refractory myeloid malignancies (ASH 2025) - P1 | "FHD-286 monotherapy induced myeloiddifferentiation in patients (pts) with relapsed/refractory (R/R) acute myeloid leukemia (AML) ormyelodysplastic syndrome (MDS), and the addition of decitabine (DAC) produced objective responses.In a multicenter, open-label, Phase 1 dose escalation study (NCT04891757), pts with R/R AML, MDS, orchronic myelomonocytic leukemia received FHD-286 monotherapy or in combination with DAC. FHD-286 induced broad immunophenotypic and transcriptional changes in leukemic blasts, consistentwith decreased stemness and increased myeloid differentiation. In the combination therapy cohort,responders exhibited stronger transcriptional impacts than nonresponders or monotherapy-treated pts.Additional studies will be needed to understand the context in which FHD-286+DAC leads to greaterefficacy, and may support pt enrichment strategies."

Clinical • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD34 • ITGAM • KIT • SMARCA4