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LGK974
N/A
Porcupine inhibitor
Hemat
LGK974 is an orally bioavailable, and selective small molecule inhibitor of Porcupine. Areas of Research: Melanoma, breast cancer, pancreatic cancer, gastrointestinal cancers and other cancers with a high level of Wingless-type (Wnt) pathway activity.

Compound DescriptionOral, selective small molecule inhibitor of Porcupine

Areas of ResearchMelanoma, breast cancer, pancreatic cancer, gastrointestinal cancers and other cancers with a high level of Wingless-type (Wnt) pathway activity

Proposed Mechanism of ActionThe canonical (β-catenin-dependent) Wnt pathway plays an important role in cellular proliferation and embryonic development.1 Dysregulation of the Wnt pathway is known to be important in a variety of malignancies, including melanoma, breast cancer, and squamous cell carcinoma.1,2,3

Interaction between Wnt ligands and the co-receptors Frizzled (Fz) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) initiates the canonical Wnt pathway.1 Wnt ligands require post-translational palmitoylation in order to be secreted and functionally active.4,5 An enzyme that is involved in regulating this process is Porcupine, a membrane bound O-acyltransferase enzyme, required and specific for palmitoylation of Wnt ligands.4,5

Inhibition of Porcupine by LGK974 blocks the palmitoylation and subsequent secretion of Wnt and hence inhibits the pathway. It is expected to be effective in the treatment of cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner, however as it acts upstream of β-catenin, it is unlikely to be efficacious in tumors harboring mutations in the downstream components such as β-catenin and adenomatous polyposis coli (APC).6

Key Preclinical DataIn cell-based models LGK974 inhibits the Wnt pathway by specifically binding to Porcupine.6 In preclinical studies LGK974 inhibition of Porcupine is associated with anti-tumor activity in a Wnt-dependent head and neck squamous cell carcinoma model (HN30). Also, in a mechanistic Wnt-driven murine breast tumor model [allografts from MMTV-Wnt1 (Mouse Mammary Tumor Virus) transgenic mice] LGK974 demonstrated activity.6

Clinical StatusA phase I study using oral LGK974 in patients with melanoma or lobular breast cancer is currently ongoing.7

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.
LGK974 is an investigational compound. Efficacy and safety have not been established.
There is no guarantee LGK974 will become commercially available.
References
  1. Rey JP, Ellies DL. Wnt modulators in the biotech pipeline. Dev Dyn. 2010;239:102–114.
  2. Turashvili G, Bouchal J, Burkadze G, et al. Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology. 2006;73:213–223.
  3. Braun KM. Cutaneous cancer stem cells: beta-catenin strikes again. Cell Stem Cell. 2008;2:406–408.
  4. Takada R, Satomi Y, Kurata T, et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell. 2006;11:791–801.
  5. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–480.
  6. Novartis, data on file, 2014.
  7. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01351103. Updated May 30, 2013. Accessed January 14, 2014.

The information contained herein was last updated on April 12, 2013.

All Compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

The search results, details, and descriptions of clinical trials viewed in this app are supplied by ClinicalTrials.gov and EUtrialregistry.com. This information is maintained by a third party over whom Novartis Pharmaceuticals Corporation has no control. As such, Novartis Pharmaceuticals Corporation does not guarantee the accuracy, completeness, adequacy, or any other aspect of the information contained on this site.