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    DRUG CLASS:

    eIF4A1 inhibitor

    Related drugs:
    27d
    Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia. (PubMed, Blood Neoplasia)
    Using 3 in vivo xenograft models derived from patients with relapsed/refractory AML, the combination significantly suppressed the tumor burden and prolonged survival. These results support eIF4A-mediated protein translation as a therapeutic target in AML and highlight the potential of zotatifin and venetoclax in relapsed/refractory disease.
    Journal
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    MCL1 (Myeloid cell leukemia 1)
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    Venclexta (venetoclax) • zotatifin (eFT226)
    29d
    Combinational Inhibition of the eIF4F Complex, AKT1, and EZH2 Enhances Anticancer Effects in BRAFV600E Mutant A375 Melanoma Cells. (PubMed, Oncol Res)
    Melanoma A375 (vemurafenib [VEM]-sensitive) and A375R (VEM-resistant) cells were exposed to eIF4Fi RocA at varying doses and durations in vitro...Combined CR-1-31-B, EZH2i, and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo. The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways, resulting in resistance to both eIF4Fi and VEM. Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.
    Journal • IO biomarker
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    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • MCL1 (Myeloid cell leukemia 1) • EGR1 (Early Growth Response 1) • EIF4G1 (Eukaryotic translation initiation factor 4 gamma, 1) • FOS (Fos Proto-Oncogene AP-1 Transcription Factor Subunit 2) • JUN (Jun proto-oncogene)
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    BRAF V600E • BRAF V600
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    Zelboraf (vemurafenib) • CR-1-31-B
    2ms
    Umbrella Trial of Subtype-Targeted Therapies in ER+/HER2- Breast Cancer (clinicaltrials.gov)
    P2, N=19, Completed, Jennifer Lee Caswell-Jin | Suspended --> Completed
    Trial completion
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    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
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    ER positive • HER-2 negative • HER-2 negative + ER positive
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    Piqray (alpelisib) • fulvestrant • zotatifin (eFT226) • Soltamox (tamoxifen citrate)
    9ms
    eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer. (PubMed, Proc Natl Acad Sci U S A)
    In an early clinical trial (NCT04092673), the eIF4A inhibitor zotatifin was combined with either fulvestrant or fulvestrant plus CDK4 inhibitor, abemaciclib, in patients with acquired resistance to these agents. Multiple clinical responses including a handful of durable regressions were observed, with little toxicity. Thus, eIF4A inhibition could be useful for treating ER+ breast cancer resistant to other modalities.
    Journal
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    ER (Estrogen receptor) • CCND1 (Cyclin D1)
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    Verzenio (abemaciclib) • fulvestrant • zotatifin (eFT226)
    9ms
    Umbrella Trial of Subtype-Targeted Therapies in ER+/HER2- Breast Cancer (clinicaltrials.gov)
    P2, N=19, Suspended, Stanford University | Active, not recruiting --> Suspended
    Trial suspension
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
    |
    ER positive • HER-2 negative • HER-2 negative + ER positive
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    Piqray (alpelisib) • fulvestrant • zotatifin (eFT226) • Soltamox (tamoxifen citrate)
    10ms
    Targeting EIF4A1 is effective against human intrahepatic cholangiocarcinoma. (PubMed, JHEP Rep)
    Moreover, the Bcl-xl inhibitors A-1155463 and DT2216 profoundly augmented apoptotic cell death when administered in association with zotatifin. From a clinical standpoint, these results suggest that zotatifin improves patient outcomes by inhibiting iCCA growth and reducing tumor aggressiveness. Furthermore, combining zotatifin with other drugs could represent a promising therapeutic strategy for targeting iCCA.
    Journal
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    BCL2L1 (BCL2-like 1) • EIF4G1 (Eukaryotic translation initiation factor 4 gamma, 1)
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    zotatifin (eFT226) • DT2216
    10ms
    RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov)
    P2, N=180, Recruiting, Dana-Farber Cancer Institute | Active, not recruiting --> Recruiting | N=130 --> 180 | Trial completion date: Aug 2030 --> Aug 2031 | Trial primary completion date: Aug 2027 --> Aug 2028
    Enrollment open • Enrollment change • Trial completion date • Trial primary completion date
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    ER (Estrogen receptor)
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    ER positive
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    Verzenio (abemaciclib) • letrozole • gedatolisib (PF-05212384) • zotatifin (eFT226) • metformin • samotolisib (LY3023414)
    1year
    Small-molecule RNA therapeutics to target prostate cancer. (PubMed, Cancer Cell)
    Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, "translatome therapy" provides additional strategies to treat the deadliest cancers.
    Journal
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    HIF1A (Hypoxia inducible factor 1, alpha subunit)
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    zotatifin (eFT226)
    1year
    eIF4A1 exacerbates myocardial ischemia-reperfusion injury in mice by promoting nuclear translocation of transgelin/p53. (PubMed, Acta Pharmacol Sin)
    In conclusion, eIF4A1 is a detrimental factor in myocardial I/R injury via promoting expression and nuclear translocation of Tagln and p53 and might be a potential target for myocardial I/R injury. This study highlights a novel biological role of eIF4A1 by interacting with non-translational-related factor Tagln in myocardial I/R injury.
    Preclinical • Journal • IO biomarker
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    BCL2 (B-cell CLL/lymphoma 2) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • TAGLN (Transgelin)
    over1year
    RESOLVE: Abemaciclib + Letrozole +/- Metformin or Zotatifin in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov)
    P2, N=130, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Aug 2030 | Trial primary completion date: Aug 2026 --> Aug 2027
    Enrollment closed • Trial completion date • Trial primary completion date • Combination therapy
    |
    ER (Estrogen receptor)
    |
    ER positive
    |
    Verzenio (abemaciclib) • letrozole • zotatifin (eFT226) • metformin • samotolisib (LY3023414)
    over1year
    Umbrella Trial Testing Integrative Subtype Targeted Therapeutics in Estrogen Receptor Positive, HER2-Negative Breast Cancer (clinicaltrials.gov)
    P2, N=19, Active, not recruiting, Stanford University | Recruiting --> Active, not recruiting | N=150 --> 19
    Enrollment closed • Enrollment change
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
    |
    Piqray (alpelisib) • fulvestrant • zotatifin (eFT226) • Soltamox (tamoxifen citrate)
    almost2years
    RESOLVE: Abemaciclib + Letrozole +/- Metformin or Zotatifin in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov)
    P2, N=130, Recruiting, Dana-Farber Cancer Institute | N=60 --> 130 | Trial completion date: May 2026 --> Aug 2029 | Trial primary completion date: May 2024 --> Aug 2026
    Enrollment change • Trial completion date • Trial primary completion date • Combination therapy
    |
    ER (Estrogen receptor)
    |
    Verzenio (abemaciclib) • letrozole • zotatifin (eFT226) • metformin • samotolisib (LY3023414)