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    DRUG:

    lorecivivint (SM04690)

    i
    Other names: SM04690, SM-04690
    Company:
    Biosplice Therap, Samil Pharma
    Drug class:
    Wnt signalling pathway inhibitor, pan-CLK inhibitor, DYRK1A inhibitor
    Related drugs:
    25d
    Targeting the NOTCH2/ADAM10/TCF7L2 Axis-Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer. (PubMed, Adv Sci (Weinh))
    Furthermore, use of adavivint or blockage of ADAM10/NOTCH2/TCF7L2 signaling enhances the chemosensitivity of CRC cells. Overall, this study provides a promising candidate for the development of small-molecule inhibitors and reveals a potential therapeutic target for CRC.
    Journal
    |
    CCND1 (Cyclin D1) • NOTCH2 (Notch 2) • TCF7L2 (Transcription Factor 7 Like 2) • ADAM10 (ADAM Metallopeptidase Domain 10) • TCF7 (Transcription Factor 7)
    |
    lorecivivint (SM04690)
    3ms
    Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression. (PubMed, Mol Oncol)
    Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.
    Journal
    |
    AR (Androgen receptor) • ARSI (Arylsulfatase Family Member I) • CDK1 (Cyclin-dependent kinase 1) • CLK2 (CDC Like Kinase 2) • SRSF9 (Serine And Arginine Rich Splicing Factor 9)
    |
    AR splice variant 7 • AR-V7 expression
    |
    Xtandi (enzalutamide) • lorecivivint (SM04690) • cirtuvivint (SM08502)
    1year
    A Long-Term Safety and Efficacy Study of Lorecivivint in Subjects With Osteoarthritis of the Knee (clinicaltrials.gov)
    P3, N=276, Completed, Biosplice Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Jun 2023 | Trial primary completion date: Sep 2024 --> Jun 2023
    Trial completion • Trial completion date • Trial primary completion date
    |
    lorecivivint (SM04690)
    1year
    A Study Utilizing Patient-Reported Outcomes to Evaluate the Safety and Efficacy of Lorecivivint (SM04690) for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis (STRIDES) (clinicaltrials.gov)
    P3, N=496, Active, not recruiting, Biosplice Therapeutics, Inc. | Trial completion date: Oct 2023 --> Feb 2024 | Trial primary completion date: Oct 2023 --> Feb 2024
    Trial completion date • Trial primary completion date • Patient reported outcomes
    |
    lorecivivint (SM04690)
    over1year
    Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids. (PubMed, Int J Mol Sci)
    5-Fluorouracil (5FU) is widely used as the first-line treatment of colorectal cancer (CRC). But the Wnt/β-catenin pathway inhibition with Adavivint alone or in combination with 5FU in spheroids with aberrant activation of this pathway produced a severe cytostatic effect compromising their clonogenic capacity and diminishing the stem cell markers expression. Remarkably, this combined treatment also induced the survival of a small cell subpopulation that could exit the arrest, recover SOX2 levels, and re-grow after treatment.
    Preclinical • Journal
    |
    SOX2 • WNT3 (Wnt Family Member 3)
    |
    5-fluorouracil • lorecivivint (SM04690)
    over3years
    Inhibiting Wnt/beta-catenin in CTNNB1-mutated endometrial cancer. (PubMed, Mol Carcinog)
    Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1-mutant EC.
    Journal
    |
    CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    CTNNB1 mutation
    |
    foscenvivint (PRI724) • lorecivivint (SM04690) • XAV-939