The 14-3-3 proteins are a highly conserved family of dimeric proteins that bind to phosphoserine motifs in target proteins. As such they play an important role as regulatory proteins modulating the function of key cellular proteins involved in signalling. 14-3-3 proteins have an established pro-survival role and are implicated in protecting cancer cells against apoptosis. Many binding partners of 14-3-3 have been identified to date including pro-apoptotic molecules such as BAD and ASK-1. 14-3-3 has also been shown to interact with the beta common signaling subunit of GM-CSF, IL-3 and IL-5 receptor family that is involved in the stimulation of cell survival and proliferation signals.

The crystal structure of 14-3-3 was solved in complex with a peptide ⁵⁸²HSRSLP⁵⁸⁷ mimicking the beta common binding site. The structure confirms the involvement of serine⁵⁸⁵ on beta common subunit in binding with 14-3-3 protein but the downstream implications of this interaction remain to be elucidated. Given the over-expression of 14-3-3 in cancer cells and their central role in integrating pro-survival and proliferative signalling, 14-3-3 proteins are enticing targets for anti-cancer drug development. To this end we have identified small molecule inhibitors that target the 14-3-3 dimer interface. These inhibitors make the dimeric protein susceptible to phosphorylation at the dimer interface leading to apoptosis.