LGK-974

Catalog No.S7143 Batch:S714305

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Technical Data

Formula

C23H20N6O
Molecular Weight 396.44 CAS No. 1243244-14-5
Solubility (25°C)* In vitro DMSO 79 mg/mL (199.27 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description LGK-974 (NVP-LGK974, WNT974) is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM in TM3 cells. Phase 1.
Targets
Porcn [1]
(TM3 cells)
In vitro LGK974 effectively displaces [3H]-GNF-1331 with IC50 of 1 nM in the PORCN radioligand binding assay, and shows no major cytotoxicity in cells up to 20 µM. LGK974 shows comparable inhibitory activities against all tested Wnts with IC50 ranging from 0.05 to 2.4 nM, which is consistent with the genetic loss of PORCN phenotype. [1] LGK974 specifically inhibits the growth of three RNF43-mutant cell lines, HPAF-II, PaTu 8988S, and Capan-2. [2]
In vivo In a murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30), LGK974 (3 mg/kg) inhibits Wnt signaling in vivo and induces tumor regression without significant body weight loss in the mice. [1] LGK974 (5 mg/kg, p.o., BID) also inhibits tumor growth of RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo. [2]
Features Orally bioavailable Porcupine-specific inhibitor that has been tested in Phase I clinical trials for treatment of malignancies dependent on Wnt ligands.

Protocol (from reference)

Cell Assay:

[2]
  • Cell lines

    HPAF-II, PaTu 8988S, and Capan-2 cells

  • Concentrations

    ~1 μM

  • Incubation Time

    3 days

  • Method

    Cells are plated in growth medium in a 96-well plate at a density of 6,000–12,000 cells per well and treated with DMSO or 1 μM LGK974. After 3 d, the cells are treated with fresh growth medium containing 20 μM EdU, which is included in the Click-iT EdU Alexa Fluor 488 HCS assay kit, and the plate was incubated for 2 h at 37 °C in a humidified atmosphere containing 5% CO2. Cells are fixed with final 4% (mass/vol) paraformaldehyde for 30 min, washed with PBS, permeabilized, and stained with 50 μg/mL Hoechst in PBS for 30 min. After wash, the cells are proceeded to EdU detection according to the instruction of Click-iT EdU assay kit. Triplet wells are performed for each condition.
Animal Study:

[1]
  • Animal Models

    A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30)

  • Dosages

    ~3 mg/kg daily

  • Administration

    Oral gavage

Customer Product Validation

Data from [Data independently produced by Breast Cancer Res, 2014, 16(4), 408]

Data from [Data independently produced by , , Nat Commun, 2017, 8:15945]

Data from [Data independently produced by , , J Clin Endocrinol Metab, 2015, 100(6): E836-44]

Data from [Data independently produced by , , J Endocrinol, 2018, 238(1):13-23]

Selleck's LGK-974 has been cited by 90 publications

Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress [ Nat Commun, 2024, 15(1):7404] PubMed: 39191776
Loss of ARID3A perturbs intestinal epithelial proliferation-differentiation ratio and regeneration [ J Exp Med, 2024, 221(10)e20232279] PubMed: 39150450
Physiological regulation of neuronal Wnt activity is essential for TDP-43 localization and function [ EMBO J, 2024, 43(16):3388-3413] PubMed: 38918634
Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas [ JCI Insight, 2024, 9(3)e168826] PubMed: 38175707
Higher overall survival rates of oral squamous cell carcinoma treated with metronomic neoadjuvant chemotherapy [ Am J Cancer Res, 2024, 14(3):1033-1051] PubMed: 38590400
Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [ Nat Commun, 2023, 14(1):110] PubMed: 36611031
Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma [ Nat Commun, 2023, 14(1):2262] PubMed: 37080989
WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer [ J Exp Med, 2023, 220(1)e20220503] PubMed: 36239683
The CUT&RUN suspect list of problematic regions of the genome [ Genome Biol, 2023, 24(1):185] PubMed: 37563719
The CUT&RUN suspect list of problematic regions of the genome [ Genome Biol, 2023, 24(1):185] PubMed: 37563719

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

NOT FOR HUMAN, VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.