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    DRUG:

    camibirstat (FHD-286)

    i
    Other names: FHD-286, FHD286, FHD 286
    Company:
    Foghorn Therap
    Drug class:
    SMARCA2 inhibitor, SMARCA4 inhibitor
    Related drugs:
    5ms
    Selective Sensitivity of Ph-like B-ALL to BRG1 Inhibition Reveals a Novel Targeted Therapy Strategy. (PubMed, bioRxiv)
    The pharmacologic inhibition of BRG1 using two selective inhibitors, BRM014 and FHD-286, revealed marked sensitivity in Ph-like B-ALL cell lines, whereas KMT2A -R B-ALL was resistant...These results support the advancement of BRG1-directed strategies as a viable treatment approach for patients with Ph-like B-ALL, with the potential to improve outcomes in this high-risk population. Higher levels of BRG1 correlate to poor clinical outcomes in Ph-like but KMT2A -R B-ALL Inhibition of BRG1 induces cell cycle arrest in Ph-like cells in vitro and extends the survival of mice in pre-clinical in vivo studies.
    Journal
    |
    KMT2A (Lysine Methyltransferase 2A) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CDK4 (Cyclin-dependent kinase 4) • CDK6 (Cyclin-dependent kinase 6) • CCND3 (Cyclin D3) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • E2F1 (E2F transcription factor 1)
    |
    camibirstat (FHD-286)
    8ms
    A Phase 1 Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients With Advanced Myeloid Malignancies. (PubMed, Clin Cancer Res)
    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.
    P1 data • Journal
    |
    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)
    |
    camibirstat (FHD-286)
    8ms
    FHD-286-C-002: FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies (clinicaltrials.gov)
    P1, N=144, Active, not recruiting, Foghorn Therapeutics Inc. | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    cytarabine • decitabine • camibirstat (FHD-286)
    9ms
    Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations. (PubMed, Blood Cancer J)
    This efficacy is associated with the induction of gene-expression perturbations responsible for growth inhibition, differentiation, as well as a reduced AML-initiating potential of the AML cells. Additionally, co-treatment with FHD-286 and FLT3i exerts superior pre-clinical efficacy against AML cells and patient-derived (PD) xenograft (PDX) models of AML with FLT3 mutations.
    Preclinical • Journal
    |
    FLT3 (Fms-related tyrosine kinase 3) • 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)
    |
    FLT3 mutation
    |
    camibirstat (FHD-286)
    11ms
    Discovery of FHD-286, a First-in-Class, Orally Bioavailable, Allosteric Dual Inhibitor of the Brahma Homologue (BRM) and Brahma-Related Gene 1 (BRG1) ATPase Activity for the Treatment of SWItch/Sucrose Non-Fermentable (SWI/SNF) Dependent Cancers. (PubMed, J Med Chem)
    Herein, we report the discovery of compound 1 (FHD-286) as a potent allosteric inhibitor of the dual ATPase subunits from a high-throughput screening hit with a BRM IC50 of ∼27 μM. FHD-286 is an orally bioavailable compound with antitumor activity in mouse xenograft models of uveal melanoma and acute myeloid leukemia and is being evaluated in Phase 1 clinical trials.
    Journal
    |
    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)
    |
    camibirstat (FHD-286)
    over1year
    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)
    |
    camibirstat (FHD-286)
    over1year
    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) • camibirstat (FHD-286)
    over1year
    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)
    |
    camibirstat (FHD-286)
    over1year
    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
    |
    camibirstat (FHD-286)
    almost2years
    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 • camibirstat (FHD-286)
    2years
    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)
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    FLT3 mutation • NPM1 mutation • CD123 expression
    |
    Venclexta (venetoclax) • decitabine • Revuforj (revumenib) • birabresib (OTX015) • camibirstat (FHD-286)
    2years
    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 • camibirstat (FHD-286)