^
    2d
    Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax. (PubMed, Res Sq)
    We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines...By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout...Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.
    Journal • PARP Biomarker • IO biomarker
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CHEK2 (Checkpoint kinase 2) • TP53BP1 (Tumor Protein P53 Binding Protein 1)
    |
    Venclexta (venetoclax) • Lynparza (olaparib) • Verzenio (abemaciclib) • nesuparib (JPI-547) • Modeyso (dordaviprone)
    3ms
    JPI-547, a Dual Inhibitor of PARP/Tankyrase, Shows Antitumor Activity Against Pancreatic Cancers with Homologous Recombination Repair Deficiency or Wnt-Addiction. (PubMed, Int J Biol Sci)
    JPI-547 outperformed most PARP inhibitors, with a half-maximal inhibitory concentration approximately 10-fold lower than that of olaparib. PDAC cells reliant on Wnt signaling due to pathogenic RNF43 mutations showed increased susceptibility to JPI-547 without altering homologous recombination repair efficiency. JPI-547 disrupts the Wnt/β-catenin pathway in RNF43-mutated cells and inhibits the oncogenic YAP pathway, highlighting its multifaceted therapeutic potential in PDAC with HRD or Wnt-addiction.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • RNF43 (Ring Finger Protein 43)
    |
    HRD
    |
    Lynparza (olaparib) • nesuparib (JPI-547)
    5ms
    The therapeutic potential of repurposed mebendazole, alone and in synergistic combination with ONC201, in the treatment of diffuse midline glioma. (PubMed, Am J Cancer Res)
    Finally, one pair of ONC201-sensitive and ONC201-resistant DMG cell lines with acquired resistance showed same responsiveness to MBZ with similar values of IC50 and Emax. In conclusion, MBZ demonstrates high growth-inhibitory/proapoptotic activity, chemosensitization property to ONC201 and the ability to overcome ONC201 resistance in DMG cell cultures, proposing as a new low-toxicity therapeutic for DMG, with a potential to be used in second-line treatment and/or in combination protocols.
    Journal • PARP Biomarker
    |
    CASP3 (Caspase 3) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • ANXA5 (Annexin A5)
    |
    nesuparib (JPI-547) • Modeyso (dordaviprone) • mebendazole
    8ms
    PENELOPE: First-line Carboplatin and Paclitaxel in Combination With Pembrolizumab, Followed by Maintenance Pembrolizumab With or Without Nesuparib, in Patients With Newly Diagnosed Advanced or Recurrent MMR-proficient (pMMR) Endometrial Cancer (clinicaltrials.gov)
    P2, N=92, Recruiting, Yonsei University | Not yet recruiting --> Recruiting
    Enrollment open
    |
    Keytruda (pembrolizumab) • carboplatin • paclitaxel • nesuparib (JPI-547)
    10ms
    Study to Assess the Safety, Tolerability of JPI-547 in Combination With Modified FOLFIRINOX or Gemcitabine-nab-paclitaxel in Patients With Locally Advanced and Metastatic Pancreatic Cancer (clinicaltrials.gov)
    P1, N=30, Recruiting, Onconic Therapeutics Inc. | Trial completion date: Sep 2026 --> Jun 2026
    Trial completion date
    |
    gemcitabine • 5-fluorouracil • albumin-bound paclitaxel • oxaliplatin • irinotecan • leucovorin calcium • nesuparib (JPI-547)
    11ms
    Study to Assess the Safety, Tolerability of JPI-547 in Combination With Modified FOLFIRINOX or Gemcitabine-nab-paclitaxel in Patients With Locally Advanced and Metastatic Pancreatic Cancer (clinicaltrials.gov)
    P1, N=30, Recruiting, Onconic Therapeutics Inc. | Trial completion date: Dec 2024 --> Sep 2026 | Trial primary completion date: Dec 2024 --> Mar 2026
    Trial completion date • Trial primary completion date
    |
    gemcitabine • 5-fluorouracil • albumin-bound paclitaxel • oxaliplatin • irinotecan • leucovorin calcium • nesuparib (JPI-547)
    over1year
    Study to Assess the Safety, Tolerability of JPI-547 in Combination With Modified FOLFIRINOX or Gemcitabine-nab-paclitaxel in Patients With Locally Advanced and Metastatic Pancreatic Cancer (clinicaltrials.gov)
    P1, N=24, Recruiting, Onconic Therapeutics Inc. | Not yet recruiting --> Recruiting | Trial completion date: Aug 2023 --> Dec 2024 | Trial primary completion date: Aug 2023 --> Dec 2024
    Enrollment open • Trial completion date • Trial primary completion date • Combination therapy • Metastases
    |
    gemcitabine • 5-fluorouracil • albumin-bound paclitaxel • oxaliplatin • irinotecan • leucovorin calcium • nesuparib (JPI-547)
    over1year
    A Study to Evaluate the Efficacy and Safety of JPI-547 in Platinum-resistant, Advanced/Relapsed Ovarian Cancer Subjects Previously Treated With a PARP Inhibitor (clinicaltrials.gov)
    P2, N=58, Active, not recruiting, Onconic Therapeutics Inc. | Not yet recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
    |
    nesuparib (JPI-547)
    over1year
    PENELOPE: First-line Carboplatin and Paclitaxel in Combination With Pembrolizumab, Followed by Maintenance Pembrolizumab With or Without Nesuparib, in Patients With Newly Diagnosed Advanced or Recurrent MMR-proficient (pMMR) Endometrial Cancer (clinicaltrials.gov)
    P2, N=92, Not yet recruiting, Yonsei University
    New P2 trial
    |
    Keytruda (pembrolizumab) • carboplatin • paclitaxel • nesuparib (JPI-547)
    almost2years
    ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma. (PubMed, Am J Cancer Res)
    Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.
    Journal • PARP Biomarker
    |
    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MLH1 (MutL homolog 1) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • XIAP (X-Linked Inhibitor Of Apoptosis) • ATF4 (Activating Transcription Factor 4) • CFLAR (CASP8 and FADD-like apoptosis regulator)
    |
    TP53 mutation • KRAS mutation • HER-2 amplification • PIK3CA mutation • MLH1 mutation
    |
    nesuparib (JPI-547) • Modeyso (dordaviprone)
    over2years
    JPI-547, a dual inhibitor of PARP/Tankyrase, shows promising antitumor activity against pancreatic cancers with homologous recombination repair deficiency or Wnt-addiction (AACR 2023)
    JPI-547 is a novel PARP inhibitor, simultaneously targeting tankyrase1/2, other members of the PARP family, that are involved in the Wnt/β-catenin pathway. Antiproliferative effect of JPI-547 and a variety of PARP inhibitors (olaparib, veliparib, talazoparib, niraparib, and rucaparib) were determined by MTT assay or clonogenic assay in 9 human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, HPAF-II, Capan-2, AsPC-1, SNU-410, SNU-213, SNU-324, MIA-PaCa2, and PANC-1). JPI-547 shows promising, preclinical antitumor effects against PDAC cells with HRD or Wnt-addiction, providing a rationale for further biomarker-driven clinical development of JPI-547 for the treatment of patients with PDAC.
    BRCA Biomarker • PARP Biomarker
    |
    BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • RNF43 (Ring Finger Protein 43)
    |
    HRD • RNF43 mutation
    |
    Lynparza (olaparib) • Talzenna (talazoparib) • Zejula (niraparib) • Rubraca (rucaparib) • veliparib (ABT-888) • nesuparib (JPI-547)
    over2years
    JPI-547, a novel dual inhibitor of PARP 1/2 and tankyrase 1/2 overcomes olaparib resistance in BRCA 1/2 mutant ovary and breast cancer preclinical model (AACR 2023)
    Using established olaparib resistance models, the anti-tumor efficacy of JPI-547 was compared with olaparib, niraparib, and talazoparib. Then this suppression resulted in blockade of HR repair.JPI-547 showed promising efficacy in an olaparib-resistant preclinical model. JPI-547 merits further clinical development in the PARP inhibitor-resistant ovary and breast cancer.
    Preclinical • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A)
    |
    BRCA2 mutation • BRCA1 mutation • BRCA mutation
    |
    Lynparza (olaparib) • Talzenna (talazoparib) • Zejula (niraparib) • nesuparib (JPI-547)