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    DRUG:

    FHD-286

    i
    Other names: FHD-286, FHD286, FHD 286
    Company:
    Foghorn Therap
    Drug class:
    SMARCA2 inhibitor, SMARCA4 inhibitor
    Related drugs:
    4ms
    SMARCA2 and SMARCA4 Participate in DNA Damage Repair. (PubMed, Front Biosci (Landmark Ed))
    This study reveals SMARCA2/4 as a DNA damage repair factor for double-strand break repair.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CREBBP (CREB binding protein) • RAD51 (RAD51 Homolog A) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • RNF8 (Ring Finger Protein 8)
    |
    FHD-286
    4ms
    SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing. (PubMed, J Hematol Oncol)
    This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.
    Journal
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • SRRM4 (Serine/Arginine Repetitive Matrix 4) • ASCL1 (Achaete-Scute Family BHLH Transcription Factor 1) • NEUROD1 (Neuronal Differentiation 1)
    |
    Gilotrif (afatinib) • FHD-286
    4ms
    Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer. (PubMed, Cancer Cell)
    Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.
    Journal
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • POU2F3 (POU Class 2 Homeobox 3) • ASCL1 (Achaete-Scute Family BHLH Transcription Factor 1) • NEUROD1 (Neuronal Differentiation 1)
    |
    FHD-286
    7ms
    FHD-286 in Subjects With Metastatic Uveal Melanoma (clinicaltrials.gov)
    P1, N=76, Terminated, Foghorn Therapeutics Inc. | N=125 --> 76 | Trial completion date: Aug 2025 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2023 --> Nov 2023; Sponsor terminated the study for business reasons.
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Metastases
    |
    FHD-286
    9ms
    BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor. (PubMed, Blood)
    Compared to each drug, co-treatment with FHD-286 and BETi, MI, decitabine or venetoclax 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 MLL1r or mtNPM1.
    Preclinical • Journal
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • NPM1 (Nucleophosmin 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CDK4 (Cyclin-dependent kinase 4) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    NPM1 mutation • MLL rearrangement • MLL rearrangement
    |
    Venclexta (venetoclax) • decitabine • FHD-286
    1year
    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 • PARP Biomarker • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • MCL1 (Myeloid cell leukemia 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CDK4 (Cyclin-dependent kinase 4) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD33 (CD33 Molecule) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • ITGAM (Integrin, alpha M) • BRD4 (Bromodomain Containing 4) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • CD99 (CD99 Molecule) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • HEXIM1 (HEXIM P-TEFb Complex Subunit 1) • MEF2C (Myocyte Enhancer Factor 2C) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • CLEC12A (C-Type Lectin Domain Family 12 Member A) • PBX3 (PBX Homeobox 3)
    |
    FLT3 mutation • NPM1 mutation • CD123 expression
    |
    Venclexta (venetoclax) • decitabine • revumenib (SNDX-5613) • birabresib (OTX015) • FHD-286
    1year
    Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies (ASH 2023)
    Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.
    Clinical • P1 data • Metastases
    |
    KMT2A (Lysine Methyltransferase 2A) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • MECOM (MDS1 And EVI1 Complex Locus) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    cytarabine • decitabine • FHD-286
    1year
    The dual BRG1/BRM (SMARCA4/2) inhibitor FHD-286 induces functional differentiation and splicing defects in preclinical models of acute myeloid leukemia (AML). (AACR-NCI-EORTC 2023)
    No abstract available
    Preclinical
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
    |
    FHD-286
    1year
    Leukemic stem cell differentiation visible at single-cell resolution in AML patients treated with BRG1/BRM inhibitor FHD-286. (AACR-NCI-EORTC 2023)
    No abstract available
    Clinical
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
    |
    FHD-286
    1year
    FHD286 is a BRG1/BRM ATPase inhibitor showing efficacy in NSCLC models and is applicable to NSCLC patients both as a single agent treatment and in combination with current standards of care. (AACR-NCI-EORTC 2023)
    No abstract available
    Clinical • Combination therapy
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
    |
    FHD-286
    1year
    Establishing the cellular and molecular impacts of the dual BRM/BRG1 inhibitor FHD-286 on preclinical models of non-small cell lung cancer (NSCLC). (AACR-NCI-EORTC 2023)
    No abstract available
    Preclinical
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
    |
    FHD-286
    1year
    FHD-286, a potent and selective inhibitor of BRG1 and BRM, shifts metastatic uveal melanoma tumor towards a less immunosuppressive state in patient samples. (AACR-NCI-EORTC 2023)
    No abstract available
    Clinical • Metastases
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
    |
    FHD-286
    1year
    Evaluating clinical biomarkers of FHD-286, a potent and selective inhibitor of BRG1/BRM, in metastatic uveal melanoma. (AACR-NCI-EORTC 2023)
    No abstract available
    Clinical • Metastases
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
    |
    FHD-286
    over1year
    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)
    The RP2D(s) has not yet been established. Updated dosing, safety, tolerability, PK and anti-tumor activity data will be shared at the meeting.
    P1 data • Metastases
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    FHD-286
    over1year
    FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies (clinicaltrials.gov)
    P1, N=50, Active, not recruiting, Foghorn Therapeutics Inc. | Suspended --> Active, not recruiting
    Enrollment closed • Combination therapy • Metastases
    |
    cytarabine • decitabine • FHD-286
    over1year
    The dual BRM/BRG1 (SMARCA2/4) inhibitor FHD-286 induces differentiation in preclinical models of AML (AACR 2023)
    Expanding on these findings, we have also demonstrated synergistic activity with multiple combination partners, including cytarabine and decitabine, in vitro. Elaboration of this in both CDX and PDX in vivo models also shows significant survival benefit in difficult to treat mutational backgrounds. Taken together, these findings suggest that FHD-286 is able to target blast progenitor populations that are heavily BRM/BRG1-dependent, and that combination with standard of care agents can achieve profound, mutationally agnostic antitumor activity in AML.
    Preclinical • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CD34 (CD34 molecule) • ITGAM (Integrin, alpha M) • SPI1 (Spi-1 Proto-Oncogene) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    FLT3-ITD mutation • CD34 positive
    |
    cytarabine • decitabine • FHD-286
    over1year
    Pre-clinical efficacy of targeting BAF complexes through inhibition of the dual ATPases BRG1 and BRM by FHD-286 in cellular models of AML (AACR 2023)
    Additionally, co-treatment with FHD-286 and venetoclax, decitabine or OTX015, as compared to each drug alone or vehicle control, significantly reduced AML burden and improved the 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 MLL-r, mtNPM1 or chromosome 3q26 lesions and EVI1 overexpression.
    Preclinical • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • IFNG (Interferon, gamma) • IL6 (Interleukin 6) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CDK4 (Cyclin-dependent kinase 4) • KMT2C (Lysine Methyltransferase 2C) • NOTCH2 (Notch 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CDK6 (Cyclin-dependent kinase 6) • SPI1 (Spi-1 Proto-Oncogene) • MEF2C (Myocyte Enhancer Factor 2C) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    NPM1 mutation • MLL rearrangement • MLL rearrangement • BCL2 expression • MYC expression • NOTCH2 mutation • KMT2A expression
    |
    Venclexta (venetoclax) • decitabine • birabresib (OTX015) • FHD-286
    2years
    Pre-Clinical Efficacy of Targeting Baf Complexes through Inhibition of the Dual Atpases BRG1 and BRM By FHD-286 in Cellular Models of AML of Diverse Genetic Background (ASH 2022)
    Based on these observations, and clinical efficacy of the combination of venetoclax and decitabine/azacitidine, we determined the in vitro lethal activity of co-treatment with FHD-286 and venetoclax or decitabine against AML cell lines and PD AML cells. Additionally, co-treatment with FHD-286 and venetoclax or decitabine or OTX015, as compared to each drug alone or vehicle control, significantly reduced the AML burden and improved median and overall survival of the immune-depleted 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 MLL-r, mtNPM1 or chromosome 3q26 lesions and EVI1 overexpression.
    Preclinical • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • IFNG (Interferon, gamma) • IL6 (Interleukin 6) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • KMT2C (Lysine Methyltransferase 2C) • NOTCH2 (Notch 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • ITGAM (Integrin, alpha M) • SPI1 (Spi-1 Proto-Oncogene) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    BCL2 expression • MYC expression • NOTCH2 mutation • KMT2A expression • ITGAM expression
    |
    Venclexta (venetoclax) • azacitidine • decitabine • birabresib (OTX015) • FHD-286
    2years
    Synergistic efficacy of the BRM/BRG1 ATPase inhibitor, FHD-286, and anti-PD-1 antibody in mouse syngeneic tumor models (SITC 2022)
    FHD-286 increased MHCI expression on B16F10 cells, and increases in IFNγ and Th1-type chemokine CXCL10 levels were observed in immunocompetent mice following treatment, suggesting that combinatorial activity may result from effects on both the tumor and the immune system. Conclusions FHD-286 has the potential to sensitize tumor to immune-checkpoint inhibition and represents a novel combination approach for cancer immunotherapy.
    Preclinical • PD(L)-1 Biomarker • IO biomarker
    |
    IFNG (Interferon, gamma) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    FHD-286
    over2years
    Modulation of SPI1 transcriptional program contributes to the preclinical anti-tumor activity of SMARCA4/SMARCA2 ATPase inhibitors in AML (AACR 2022)
    Using in vivo mouse models of AML, we demonstrate dose-dependent tumor growth inhibition and pharmacodynamic modulation of SPI1 target genes. Together, these data suggest that modulation of SPI1 function may, in part, provide a mechanistic basis for the clinical development of FHD-286 in AML.
    Preclinical • Late-breaking abstract
    |
    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • SPI1 (Spi-1 Proto-Oncogene) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    FHD-286