14-3-3 Targeting Cancer Therapeutics
Novel class of anti-cancer drugs targeting disruption of dimeric 14-3-3 protein
14-3-3 proteins play a critical role in integrating pro-survival signalling and enhancing proliferative pathways which are essential to cancer cells. Many studies indicate that 14-3-3 proteins are significantly up-regulated in human cancers including lung, head and neck, breast and ovarian cancer and play a role in cancer development and progression. Targeted knockdown of individual 14- 3-3 isoforms in cancer cells demonstrates the transformed phenotype is dependent on the amount of 14-3-3 in the cells. Many studies indicate that 14-3-3 proteins are significantly up-regulated in human cancers including lung, head and neck, breast and ovarian cancer and play a role in cancer development and progression.
Previous studies have demonstrated that reducing levels of 14-3-3 reverses the oncogenic state but does not affect normal cells. Thus regimes that effectively reduce the amount of 14-3-3 in the cell have a therapeutic benefit in cancer. It has been demonstrated sphingosine lipid binds to dimeric 14-3-3 at the dimer interface, thus allowing kinases access to a buried phosphorylation site. Subsequent phosphorylation disrupts the dimeric 14-3-3 protein and thereby causes apoptosis.
With our unique screening method we have identified two families of small molecules that mimic the actions of sphingosine and are thus capable of disrupting dimeric 14-3-3.
We are currently developing these leads with the intent to establish orally available drugs for the treatment of solid tumours, in particular non-small cell lung cancer and glioblastoma multiforme.
The screening method is currently filed as a PCT application - WO 2011/120082 For the identified families of compounds two provisional Australian patent applications have been filed.
We are seeking co-development partners and technology licensees for the development of anti-cancer therapeutics.
- Dr Joanna Woodcock, SA Pathology
- Associate Professor Stuart Pitson, SA Pathology
- Professor Angel Lopez, SA Pathology
Commercial lead UniSA Ventures