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    4ms
    Dual-target EZH2 inhibitor: latest advances in medicinal chemistry. (PubMed, Future Med Chem)
    Dual-target inhibitors, exemplified by EZH1/2 inhibitor HH-2853(28), offer enhanced efficacy and reduced adverse effects. This review highlights recent advancements in dual inhibitors targeting EZH2 and other proteins like BRD4, PARP1, and EHMT2, emphasizing rational design, structure-activity relationships, and safety profiles, suggesting their potential in clinical applications.
    Review • Journal • PARP Biomarker
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • BRD4 (Bromodomain Containing 4)
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    HH2853
    7ms
    Evaluate the Safety and Clinical Activity of HH2853 (clinicaltrials.gov)
    P1/2, N=254, Recruiting, Haihe Biopharma Co., Ltd. | N=168 --> 254
    Enrollment change • Metastases
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    ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1)
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    ARID1A mutation • BAP1 mutation • EZH2 mutation • SMARCA4 mutation
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    HH2853
    8ms
    Evaluate the Safety and Clinical Activity of HH2853 (clinicaltrials.gov)
    P1/2, N=168, Recruiting, Haihe Biopharma Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025
    Trial completion date • Trial primary completion date • Metastases
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    ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1)
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    ARID1A mutation • BAP1 mutation • EZH2 mutation • SMARCA4 mutation
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    HH2853
    1year
    A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial of HH2853 in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-Cell Lymphoma (ASH 2023)
    The 6-month OS rates was 91.97% (95%CI: 71.50%, 97.93%). Conclusions The selective EZH1/2 dual inhibitor HH2853 demonstrated good safety and promising efficacy in r/r PTCL patients, indicating its potential as a therapeutic option for this difficult to treat patient population.
    Clinical • P1 data
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
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    HH2853
    over1year
    Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition. (PubMed, Acta Pharmacol Sin)
    We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.
    Journal
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    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • GPX4 (Glutathione Peroxidase 4) • HSPA5 (Heat Shock Protein Family A (Hsp70) Member 5)
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    EZH2 wild-type
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    Tazverik (tazemetostat) • erastin • HH2853
    over1year
    HH2853, an EZH1/2 inhibitor, in patients with epithelioid sarcoma: Preliminary results from the phase 1 part of a first-in-human phase I/II study. (ASCO 2023)
    Tazemetostat (an EZH2 inhibitor) has been approved by FDA for clinical use in ES. HH2853 showed an acceptable safety profile and promising anti-tumor activity in heavily pretreated ES pts with a wide therapeutic window, providing evidence for further investigation. Clinical trial information: NCT04390737.
    Clinical • P1/2 data
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
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    Tazverik (tazemetostat) • HH2853
    over1year
    Preliminary results from the Phase I part of a first-in-human Phase I/II study of HH2853, an EZH1/2 inhibitor, in patients with relapsed/refractory non-Hodgkin lymphomas or advanced solid tumors (AACR 2023)
    HH2853 is a novel selective EZH1/2 dual inhibitor, which has demonstrated superior anti-tumor efficacy to tazemetostat (EZH2 inhibitor approved by FDA) in various preclinical models. This is a first-in-human, open-label, multi-center, phase (Ph) I/II study of HH2853 in patients (pts) with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHLs) or advanced solid tumors. This first-in-human study of HH2853 showed a manageable safety profile and promising anti-tumor activity in multiple tumor types, supporting further exploration in NHLs and solid tumors after recommended Ph II dose is determined.Clinical trial information: NCT04390737
    Clinical • P1/2 data • Metastases
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
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    Tazverik (tazemetostat) • HH2853
    2years
    Valemetostat: First approval as a dual inhibitor of EZH1/2 to treat adult T-cell leukemia/lymphoma. (PubMed, Drug Discov Ther)
    Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell lymphoma with a poor prognosis. Several other dual EZH1/2 inhibitors such as HH2853, HM97594, and HM97662 have also demonstrated potential in treating malignant tumors. Dual targeting EZH1/2 may have promising antitumor action in hematological malignancies and solid tumors.
    Journal
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
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    Ezharmia (valemetostat) • HM97594 • HH2853 • HM97662
    over2years
    Evaluate the Safety and Clinical Activity of HH2853 (clinicaltrials.gov)
    P1/2, N=188, Recruiting, Haihe Biopharma Co., Ltd. | Phase classification: P1 --> P1/2 | N=30 --> 188 | Trial completion date: Jun 2023 --> Dec 2024 | Trial primary completion date: Jun 2022 --> Dec 2023
    Phase classification • Enrollment change • Trial completion date • Trial primary completion date
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    ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1)
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    ARID1A mutation • BAP1 mutation • EZH2 mutation • SMARCA4 mutation
    |
    HH2853