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    DRUG:

    peposertib (M3814)

    i
    Other names: M3814, MSC2490484A, M 3814, M-3814, MSC-2490484A, MSC-2490484A
    Company:
    EMD Serono
    Drug class:
    DNA PK inhibitor
    Related drugs:
    18d
    Targeting the Non-Homologous End-Joining Pathway Sensitizes MDM2-Amplified Liposarcoma to Doxorubicin by Enhancing p53-Mediated Senescence. (PubMed, Cancer Res)
    Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor) or doxorubicin...Genetic perturbation of TDP2 or pharmacological inhibition of DNA-PKcs using peposertib synergized with prolonged administration of low-dose doxorubicin to induce cell cycle arrest and senescence, and subsequent senolytic treatment with Bcl2 inhibitor navitoclax triggered senescent cells to undergo apoptosis...These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of low-dose doxorubicin in DDLPS, highlighting a potential therapeutic strategy exploiting p53-mediated cell cycle arrest and senescence. Furthermore, this study provides evidence of maintained baseline p53 activity in MDM2-amplified DDLPS.
    Journal
    |
    CCNE1 (Cyclin E1) • MDM2 (E3 ubiquitin protein ligase) • CDK2 (Cyclin-dependent kinase 2) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit) • E2F3 (E2F transcription factor 3)
    |
    Ibrance (palbociclib) • doxorubicin hydrochloride • navitoclax (ABT 263) • peposertib (M3814)
    1m
    Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov)
    P1/2, N=103, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting
    Enrollment closed • Tumor mutational burden
    |
    Bavencio (avelumab) • peposertib (M3814)
    2ms
    Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov)
    P1/2, N=103, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Jul 2027 | Trial primary completion date: Dec 2025 --> Jul 2027
    Trial completion date • Trial primary completion date • Tumor mutational burden
    |
    Bavencio (avelumab) • peposertib (M3814)
    3ms
    Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov)
    P1, N=48, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting
    Enrollment closed
    |
    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • CD4 (CD4 Molecule)
    |
    cytarabine • etoposide IV • mitoxantrone • peposertib (M3814) • Starasid (cytarabine ocfosfate)
    3ms
    NRG-HN008: Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin (clinicaltrials.gov)
    P1, N=21, Active, not recruiting, National Cancer Institute (NCI) | N=42 --> 21 | Trial completion date: Dec 2025 --> Dec 2026
    Enrollment change • Trial completion date
    |
    CD4 (CD4 Molecule)
    |
    peposertib (M3814)
    4ms
    Testing the Addition of An Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Pancreatic Neuroendocrine Tumors (clinicaltrials.gov)
    P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Jun 2026 | Trial primary completion date: Oct 2025 --> Jun 2026
    Trial completion date • Trial primary completion date
    |
    peposertib (M3814) • Lutathera (lutetium Lu 177 dotatate)
    4ms
    Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov)
    P1/2, N=103, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended
    Trial suspension • Tumor mutational burden
    |
    Bavencio (avelumab) • peposertib (M3814)
    5ms
    Combined DNA-PK and PARP Inhibition as a Therapeutic Strategy in BRCA-Mutated Prostate Cancer: An in Vitro Pilot Study. (PubMed, Technol Cancer Res Treat)
    Scramble LNCaP, BRCA1 KO, and BRCA2 KO cells were treated with the PARPi talazoparib, the DNA-PK inhibitor nedisertib and their combination. Therapeutically targeting NHEJ presents a promising approach in treating BRCA-mutated PCa. Further in vivo investigations are required to assess the tolerability of this drug combination.
    Preclinical • Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BRCA (Breast cancer early onset) • ANXA5 (Annexin A5)
    |
    BRCA mutation
    |
    Talzenna (talazoparib) • peposertib (M3814)
    5ms
    Peposertib and Radiation Therapy, Followed by Temozolomide for the Treatment of Patients With Newly Diagnosed MGMT Unmethylated Glioblastoma or Gliosarcoma (clinicaltrials.gov)
    P1, N=29, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2025 --> Dec 2027 | Trial primary completion date: Oct 2025 --> Dec 2027
    Trial completion date • Trial primary completion date
    |
    MGMT (6-O-methylguanine-DNA methyltransferase)
    |
    IDH wild-type
    |
    temozolomide • peposertib (M3814)
    7ms
    NRG-HN008: Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin (clinicaltrials.gov)
    P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Sep 2025 --> Dec 2025
    Trial completion date • Trial primary completion date
    |
    CD4 (CD4 Molecule)
    |
    peposertib (M3814)
    9ms
    Targeting Artemis Sensitizes B Cells to Topoisomerase 2 Poisons by Disrupting DNA-PKcs-Dependent Repair. (PubMed, Res Sq)
    Inhibition of the Artemis activator, DNA-PKcs, with peposertib (M3814) sensitizes B cells to Top2 poisons while ATM or ATR inhibition does not...Clinical data demonstrates that high Artemis expression correlates with poor survival in several cancers, and we demonstrate that Artemis function is critical for survival following combination drug treatment. These insights can be leveraged to unlock new avenues for the treatment of aggressive cancers by enhancing the cytotoxicity of agents through blockade of DNA break repair.
    Journal
    |
    TOP2A (DNA topoisomerase 2-alpha)
    |
    peposertib (M3814)
    9ms
    Targeting synthetic lethality between non-homologous end joining and radiation in very-high-risk medulloblastoma. (PubMed, Cell Rep Med)
    Both genetic and pharmacological perturbation of DNA-PK enhance radiosensitivity in TP53-deficient SHH medulloblastoma, leading to cell death. In vivo treatment of both somatic and germline TP53-mutant SHH medulloblastoma models with peposertib, a small-molecule inhibitor of DNA-PK, significantly improves survival when combined with radiotherapy, strongly supporting further clinical investigation.
    Journal
    |
    TP53 (Tumor protein P53) • SHH (Sonic Hedgehog Signaling Molecule)
    |
    TP53 mutation
    |
    peposertib (M3814)