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    DRUG:

    ONCT-216

    i
    Other names: ONCT-216, TK-216, TK216, SPH8216
    Company:
    Oncternal Therap, Shanghai Pharma
    Drug class:
    ETS inhibitor, EWS-FLI1 inhibitor
    5ms
    Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma. (PubMed, J Clin Oncol)
    TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.
    P1/2 data • Journal
    |
    FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)
    |
    vincristine • ONCT-216
    8ms
    A Clinical Study of TK216 in Patients With Relapsed or Refractory Ewing's Sarcoma (clinicaltrials.gov)
    P2, N=30, Recruiting, Shanghai Pharmaceuticals Holding Co., Ltd | Not yet recruiting --> Recruiting
    Enrollment open
    |
    ONCT-216
    1year
    The Small-Molecule E26-Transformation-Specific Inhibitor TK216 Attenuates the Oncogenic Properties of Pediatric Leukemia. (PubMed, Genes (Basel))
    Priming the leukemic cells with 5-Azacitidine enhanced the cytotoxic effects of TK216 on pediatric leukemia cells...Consistent with this, TK216 also potentiated the cytotoxic effects of Bcl-2 inhibition in venetoclax-resistant cells. The sustained survival benefit provided to leukemic cells in the presence of bone-marrow-derived conditioned media is also found to be modulated by TK216. Taken together, our data indicates that TK216 could be a promising targeted therapeutic agent for the treatment of acute myeloid and B-lymphoid leukemia.
    Journal
    |
    MCL1 (Myeloid cell leukemia 1)
    |
    Venclexta (venetoclax) • azacitidine • ONCT-216
    2years
    ETS-Transcription Factor inhibitors are effective in TERT promoter mutated meningioma cells in vitro (EANO 2022)
    Conclusion : In summary, our results indicate that ETS transcription factor inhibition by TK216 exerts antitumour activity in our TERT promoter mutant meningioma cell model. Additionally, the sensitivity against TK216 is superior to YK-4-279 and therefore TK216 may represent a promising new therapeutic option for patients with aggressive, TERT promoter mutated meningioma.
    Preclinical • PARP Biomarker
    |
    PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • TERT (Telomerase Reverse Transcriptase) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • ANXA5 (Annexin A5)
    |
    TP53 mutation • TERT mutation • TERT promoter mutation • PARP1 expression
    |
    Oncomine™ Comprehensive Assay v3M
    |
    ONCT-216
    2years
    TK216 targets microtubules in Ewing sarcoma cells. (PubMed, Cell Chem Biol)
    Using reconstituted microtubule (MT) polymerization in vitro and cell-based chemical probe competition assays, we demonstrate that TK216 acts as an MT destabilizing agent. This work defines the mechanism of cytotoxicity of TK216, explains the synergy observed with vincristine, and calls for a reexamination of ongoing clinical trials with TK216.
    Journal
    |
    EWSR1 (EWS RNA Binding Protein 1) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)
    |
    EWSR1-FLI1 fusion
    |
    vincristine • ONCT-216
    over2years
    TK216-01: TK216 in Patients With Relapsed or Refractory Ewing Sarcoma (clinicaltrials.gov)
    P1/2, N=85, Terminated, Oncternal Therapeutics, Inc | N=45 --> 85 | Trial completion date: Mar 2024 --> Jun 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2023 --> May 2022
    Enrollment change • Trial completion date • Trial termination • Trial primary completion date
    |
    EWSR1 (EWS RNA Binding Protein 1) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)
    |
    ONCT-216
    over2years
    TK216-01: TK216 in Patients With Relapsed or Refractory Ewing Sarcoma (clinicaltrials.gov)
    P1/2, N=45, Active, not recruiting, Oncternal Therapeutics, Inc | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    EWSR1 (EWS RNA Binding Protein 1) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)
    |
    ONCT-216
    3years
    Schlafen 11 expression in human acute leukemia cells with gain-of-function mutations in the interferon-JAK signaling pathway. (PubMed, iScience)
    In these cells, the clinical JAK inhibitors cerdulatinib, ruxolitinib, and tofacitinib reduced SLFN11 expression, but IFN did not further induce SLFN11 despite phosphorylated STAT1...Accordingly, the AKT and ERK inhibitors MK-2206 and SCH77284 suppressed SLFN11 expression...Moreover, SLFN11 expression was inhibited by the ETS inhibitor TK216. Our study reveals that SLFN11 expression is regulated via the JAK, AKT and ERK, and ETS axis. Pharmacological suppression of SLFN11 warrants future studies.
    Journal
    |
    SLFN11 (Schlafen Family Member 11) • ETS1 (ETS Proto-Oncogene 1) • STAT1 (Signal Transducer And Activator Of Transcription 1)
    |
    SLFN11 expression • SLFN11 overexpression
    |
    Jakafi (ruxolitinib) • MK-2206 • ONCT-216 • tofacitinib
    3years
    TK216 in Patients With Relapsed or Refractory Ewing Sarcoma (clinicaltrials.gov)
    P1/2, N=45, Recruiting, Oncternal Therapeutics, Inc | Phase classification: P1 --> P1/2 | Trial completion date: Jun 2022 --> Mar 2024 | Trial primary completion date: Mar 2022 --> Dec 2023
    Clinical • Phase classification • Trial completion date • Trial primary completion date
    |
    EWSR1 (EWS RNA Binding Protein 1) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)
    |
    ONCT-216
    over3years
    TK216 in Patients With Relapsed or Refractory Ewing Sarcoma (clinicaltrials.gov)
    P1, N=45, Recruiting, Oncternal Therapeutics, Inc | Trial completion date: Jun 2021 --> Jun 2022 | Trial primary completion date: Mar 2021 --> Mar 2022
    Clinical • Trial completion date • Trial primary completion date
    |
    EWSR1 (EWS RNA Binding Protein 1) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)
    |
    ONCT-216