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    DRUG:

    NXP800

    i
    Other names: NXP800, NXP 800, NXP-800, CCT361814
    Company:
    Cancer Therapeutics CRC, Nuvectis Pharma
    Drug class:
    GCN2 activator
    Related drugs:
    9ms
    From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma (AACR-NCI-EORTC 2023)
    No abstract available
    Clinical
    |
    ARID1A (AT-rich interaction domain 1A)
    |
    ARID1A mutation
    |
    NXP800
    12ms
    HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies. (PubMed, J Med Chem)
    Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies.
    Journal
    |
    HSF1 (Heat Shock Transcription Factor 1)
    |
    NXP800
    1year
    A Phase 1 Clinical Study of NXP800 in Subjects With Advanced Cancers and Expansion in Subjects With Ovarian Cancer (clinicaltrials.gov)
    P1, N=61, Recruiting, Nuvectis Pharma, Inc. | N=17 --> 61 | Trial completion date: Apr 2023 --> Jun 2025 | Trial primary completion date: Jan 2023 --> Dec 2024
    Enrollment change • Trial completion date • Trial primary completion date • Metastases
    |
    ARID1A (AT-rich interaction domain 1A) • BRCA (Breast cancer early onset)
    |
    ARID1A mutation • BRCA mutation
    |
    NXP800
    1year
    Activation of the integrated stress response by the developmental HSF1 pathway inhibitor NXP800 (AACR 2023)
    Using an siRNA approach to determine if activation of the ISR components was contributing to growth inhibition following NXP800 exposure, we found that blocking the induction of ATF4 reduced the response of NXP800-sensitive SK-OV-3 human ovarian carcinoma cells to NXP800 treatment.In summary, NXP800 acts on cancer cells to induce activation of the ISR pathway via GCN2, which then leads to inhibition of HSF1 activation. Further studies are underway to determine the precise molecular target of NXP800 and the mechanism of HSF1 pathway inhibition.
    Late-breaking abstract
    |
    ATF4 (Activating Transcription Factor 4) • CHAC1 (ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1) • HSF1 (Heat Shock Transcription Factor 1)
    |
    NXP800
    1year
    Inhibition of HSF1 demonstrates therapeutic efficacy in preclinical models of cholangiocarcinoma (AACR 2023)
    NXP800, a HSF1 inhibitor, demonstrated significant therapeutic activity in a cholangiocarcinoma PDX. Further studies are needed and being performed to determine the role of HSF1 inhibition in human cholangiocarcinoma.
    Preclinical • Tumor mutational burden
    |
    TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR1 (Fibroblast growth factor receptor 1) • AR (Androgen receptor) • ARID1A (AT-rich interaction domain 1A) • HSF1 (Heat Shock Transcription Factor 1)
    |
    NRAS mutation • ARID1A mutation • FGFR2 mutation • FGFR1 mutation • NRAS Q61 • AR overexpression • FGFR2 overexpression • AR expression • FGFR2 expression
    |
    NXP800
    over1year
    NXP800 versus cisplatin in ARID1a-mutated Ovarian Clear Cell Carcinoma xenograft models (ESMO-GC 2023)
    Planned phase 1b expansion cohorts will include ovarian clear cell carcinoma and ovarian endometrioid carcinoma patients with ARID1A mutation. Legal entity responsible for the study The authors.
    Preclinical
    |
    ARID1A (AT-rich interaction domain 1A) • HSF1 (Heat Shock Transcription Factor 1)
    |
    ARID1A mutation
    |
    cisplatin • NXP800
    over1year
    Discovery and validation of biomarkers to support clinical development of NXP800: A first-in-class orally active, small-molecule HSF1 pathway inhibitor (AACR-NCI-EORTC 2022)
    Conclusions A Phase 1 trial (NCT05226507) of NXP800 is underway, incorporating the validated predictive, PK and PD biomarkers that constitute a Pharmacological Audit Trail. Future expansion cohorts will include patients with ARID1A mutation, including ovarian clear cell carcinoma and ovarian endometrioid carcinoma.
    Clinical
    |
    ARID1A (AT-rich interaction domain 1A) • ATF4 (Activating Transcription Factor 4) • ATF3 (Activating Transcription Factor 3) • HSF1 (Heat Shock Transcription Factor 1)
    |
    ARID1A mutation
    |
    NXP800