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Synaptojanin2 inhibitors for cancer

Technology Number: 

1668

Principal Investigator

Prof.
Yosef
Yarden

Department: 

Biological Regulation

Patent Status: 

Granted US 8399413; 8232250; 8969302; 9402874; 9155776
Summary 

Despite progress in early detection and treatment, breast cancer remains a leading cause of cancer-related death in women. For example, in 2012 alone, 41,150 women in the United States died from breast cancer.

Targeted therapies, which are based on oncogenic genetic abnormalities, are commonly used to treat subgroups of breast cancer patients. Although these treatments show promising results, they are limited to only a subgroup of patients (for example, amplification of HER2 occurs in about 15% of breast cancers) and there is an unmet need for the identification of druggable targets with a major oncogenic role in breast cancer development.

The present invention relates to the identification of SYNJ2 as a novel target for breast cancer treatment. SYNJ2 expression is enhanced in a sub-population of breast cancer patients and its catalytic activity was shown to promoted cell migration and invasion. Furthermore, screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration, suggesting that SYNJ2 is a potential target for cancer treatment.

Applications


 


Advantages


  • Novel identification of SYNJ2 as a genetically aberrant and potentially druggable driver of tumor progression.
  • Specificity – the discovered SYNJ2 inhibitors do not inhibit SYNJ1 which plays additional roles in the nervous system.
  • Potential therapeutic effect – Inhibition of SYNJ2 in several cancer models blocks tumor progression and invasion.


Technology's Essence


SYNJ2 abundance is increased in breast tumors and it is correlated with poor prognosis and aggressive subtypes of breast cancer. Furthermore, growth factors involved in breast cancer metastasis can increase SYNJ2 expression in association with increased cell invasion.

SYNJ2 is localized to cellular protrusions involved in migration and matrix invasion and its phosphatase activity enhances tumor growth and metastasis in mice. Unlike wild-type SYNJ2, reexpression of a catalytic inactive mutant failed to restore invasiveness of cancer cells, indicating that the catalytic activity of SYNJ2 is essential for motility.

Using a high-throughput screening platform for the measurement of SYNJ2 activity, four specific SYNJ2 inhibitors were discovered. All of the four inhibitors were selective to SYNJ2 and didn’t have an effect on its brain-enriched kin, SYNJ1. In addition, all four compounds attenuated cellular invasion, suggesting that specific SYNJ2 inhibitors can be developed as potential drugs for cancer therapy.

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