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    DRUG CLASS:

    PARG inhibitor

    Related drugs:
    4ms
    ERADIC8: A Study of PARG Inhibitor ETX-19477 in Patients With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=120, Recruiting, 858 Therapeutics, Inc. | Phase classification: P1 --> P1/2 | N=48 --> 120 | Trial primary completion date: Dec 2025 --> Dec 2026
    Phase classification • Enrollment change • Trial primary completion date
    |
    BRCA (Breast cancer early onset)
    4ms
    Study of SYN608 for the Treatment of Advanced or Metastatic Solid Tumors (clinicaltrials.gov)
    P1, N=105, Not yet recruiting, Hangzhou SynRx Therapeutics Biomedical Technology Co., Ltd
    New P1 trial
    |
    BRCA (Breast cancer early onset)
    7ms
    A Phase I/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of XNW29016 Tablets in Advanced Solid Tumors With Failed Standard Treatment (clinicaltrials.gov)
    P1/2, N=132, Recruiting, Evopoint Biosciences Inc.
    New P1/2 trial
    12ms
    Prospects for PARG inhibitors in cancer therapy. (PubMed, J Mol Cell Biol)
    PARG is a significant molecular target for treating PAR-related cancers. This review provides a comprehensive overview of the physiological role of PARG and the development of its inhibitors, highlighting its potential as an innovative target for cancer treatment.
    Journal
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    PARP1 (Poly(ADP-Ribose) Polymerase 1)
    1year
    PARG inhibitor sensitivity correlates with accumulation of single-stranded DNA gaps in preclinical models of ovarian cancer. (PubMed, Proc Natl Acad Sci U S A)
    Regardless of the BRCA/HRD-status, the induction of ssGAPs in preclinical models of ovarian cancer cells correlates with PARGi sensitivity. Patient-derived organoids (PDOs) may be a useful model system for testing PARGi sensitivity and functional biomarkers.
    Preclinical • Journal • BRCA Biomarker • PARP Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
    |
    BRCA2 mutation • BRCA1 mutation • HRD • BRCA mutation • PARP1 mutation
    1year
    A Study of PARG Inhibitor IDE161 in Participants with Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=216, Recruiting, IDEAYA Biosciences | N=68 --> 216 | Trial completion date: Sep 2025 --> May 2027 | Trial primary completion date: Jun 2025 --> Oct 2026
    Enrollment change • Trial completion date • Trial primary completion date
    |
    HRD (Homologous Recombination Deficiency)
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    HRD
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    Keytruda (pembrolizumab) • IDE161
    1year
    PARG inhibition induces nuclear aggregation of PARylated PARP1. (PubMed, Structure)
    Finally, we find that PARP1 nuclear aggregates were highly persistent and were associated with cleaved cytoplasmic PARP1, ultimately leading to cell death. Overall, our data uncover an unexpected mechanism of PARG inhibitor cytotoxicity, which will shed light on the use of these drugs as anti-cancer therapeutics.
    Journal
    |
    PARP1 (Poly(ADP-Ribose) Polymerase 1)
    1year
    A PARG Inhibitor DAT-2645 Monotherapy in Patients with Advanced/Metastatic Solid Tumors Harboring BRCA1/2 Loss of Function Alterations And/or Other Defects in the DDR Pathway (clinicaltrials.gov)
    P1, N=112, Not yet recruiting, Danatlas Pharmaceuticals Co., Ltd
    New P1 trial • Metastases
    |
    BRCA (Breast cancer early onset)
    1year
    Synergistic Effect of Ubiquitin-Specific Protease 14 and Poly(ADP-Ribose) Glycohydrolase Co-Inhibition in BRCA1-Mutant, Poly(ADP-Ribose) Polymerase Inhibitor-Resistant Triple-Negative Breast Cancer Cells. (PubMed, Onco Targets Ther)
    IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc. USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BRCA (Breast cancer early onset) • TP53BP1 (Tumor Protein P53 Binding Protein 1) • USP14 (Ubiquitin Specific Peptidase 14)
    |
    BRCA1 mutation • MYC expression • BRCA mutation • PARP1 mutation
    over1year
    Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation. (PubMed, NAR Cancer)
    In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.
    Review • Journal
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    TYMS (Thymidylate Synthetase)
    over1year
    Oncometabolite 2-hydroxyglutarate suppresses basal protein levels of DNA polymerase beta that enhances alkylating agent and PARG inhibition induced cytotoxicity. (PubMed, DNA Repair (Amst))
    The standard treatment for GBM includes radiation combined with temozolomide, an alkylating agent...However, the overproduction of 2-hydroxyglutarate, an oncometabolite produced by the IDH1 R132H mutant protein, suppresses BER capacity by reducing Polβ protein levels. This defines a novel mechanism by which the IDH1 mutation in gliomas confers cellular sensitivity to alkylating agents and to inhibitors of the poly-ADP-ribose glycohydrolase, PARG.
    Journal • PARP Biomarker
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    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • XRCC1 (X-Ray Repair Cross Complementing 1) • PARP2 (Poly(ADP-Ribose) Polymerase 2)
    |
    temozolomide
    over1year
    ERADIC8: A Study of PARG Inhibitor ETX-19477 in Patients With Advanced Solid Malignancies (clinicaltrials.gov)
    P1, N=48, Recruiting, 858 Therapeutics, Inc.
    New P1 trial • Metastases
    |
    BRCA (Breast cancer early onset)