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    DRUG CLASS:

    DYRK1A inhibitor

    Related drugs:
    6ms
    Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A. (PubMed, Nat Genet)
    Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
    Journal
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    DYRK1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A)
    6ms
    LEUCETTA: Leucettinib-21 First-in-Human Phase 1 in Healthy Volunteers and Subjects With Down Syndrome and Alzheimer's Disease (clinicaltrials.gov)
    P1, N=120, Recruiting, Perha Pharmaceuticals | Trial completion date: Aug 2024 --> Jul 2025 | Trial primary completion date: Aug 2024 --> Jul 2025
    Trial completion date • Trial primary completion date
    11ms
    DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma. (PubMed, Dev Cell)
    Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver cancer models, including xenografts, patient-derived xenografts, and spontaneous tumor model. Our study elucidates how the DYRK1A-TGF-β signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver cancer therapy.
    Journal
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    SLC1A5 (Solute Carrier Family 1 Member 5) • TGFB1 (Transforming Growth Factor Beta 1) • SMAD3 (SMAD Family Member 3)
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    IACS-010759
    12ms
    THE FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle. (PubMed, bioRxiv)
    In addition, Fam53C knockout mice show defects in body growth and behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.
    Journal
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    CDK4 (Cyclin-dependent kinase 4)
    1year
    Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR. (PubMed, Nat Commun)
    Here we confirm four known associations (BRAF, SLC35A2, MTOR, PTPN11), support eight associations without prior statistical support (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS), and identify novel associations for two genes, DYRK1A and EGFR. Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable targets.
    Journal
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    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • FGFR1 (Fibroblast growth factor receptor 1) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SLC35A2 (Solute Carrier Family 35 Member A2) • DYRK1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A) • RHEB (Ras Homolog, MTORC1 Binding)
    1year
    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
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    CCND1 (Cyclin D1) • NOTCH2 (Notch 2) • TCF7L2 (Transcription Factor 7 Like 2) • ADAM10 (ADAM Metallopeptidase Domain 10) • TCF7 (Transcription Factor 7)
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    lorecivivint (SM04690)
    1year
    Design, synthesis, and structure-activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors. (PubMed, RSC Med Chem)
    Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a-m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.
    Journal
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    DYRK1B (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B)
    1year
    Differential regulation of expression of the protein kinases DYRK1A and DYRK1B in cancer cells. (PubMed, Sci Rep)
    Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases.
    Journal
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    AURKA (Aurora kinase A) • AURKB (Aurora Kinase B) • DYRK1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A) • DYRK1B (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B)
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    alisertib (MLN8237) • barasertib-HQPA (AZD2811) • tozasertib (MK-0457)
    1year
    Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B. (PubMed, J Med Chem)
    Compared to competitive kinase inhibition, targeted degradation of DYRK1 by DYR684 provided improved suppression of downstream signaling. Collectively, our results identify DYRKs as viable targets for PROTAC-mediated degradation and qualify DYR684 as a useful chemical probe for DYRK1A and DYRK1B.
    Journal
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    CRBN (Cereblon) • DYRK1B (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B)
    1year
    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
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    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)
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    AR splice variant 7 • AR-V7 expression
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    Xtandi (enzalutamide) • lorecivivint (SM04690) • cirtuvivint (SM08502)
    over1year
    Targeting the DYRK1A kinase prevents cancer progression and metastasis and promotes cancer cells response to G1/S targeting chemotherapy drugs. (PubMed, NPJ Precis Oncol)
    Furthermore, we show that accumulation of cancer cells in G1/S upon DYRK1A inhibition led to significant potentiation of G1/S targeting chemotherapy drug responses in vitro and in vivo. This study underscores the potential for developing novel DYRK1A-targeting therapies in colon and breast cancers and, at the same time, further defines DYRK1A pharmacological inhibition as a viable and powerful combinatorial treatment approach for improving G1/S targeting chemotherapy drugs treatments in solid tumors.
    Journal
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    DYRK1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A)
    almost2years
    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, Completed, Biosplice Therapeutics, Inc. | Active, not recruiting --> Completed
    Trial completion • Patient reported outcomes