Determining the mechanism of action of a novel histone deacetylase 6 specific inhibitor that kills chemoresistant breast cancer

The majority of cytotoxic agents used to treat people with tumours kill cells via the mitochondrial pathway of cell death. Previously, I found that primary tumours that are chemoresistant in vivo usually contain mitochondria that are resistant to apoptotic signalling. We performed a small molecule screen to identify new therapeutic small molecules that can preferentially kill cancer cells independent of mitochondrial apoptosis and identified the first reported case of a specific novel histone deacetylase 6 (HDAC6) inhibitor. HDAC6 deacetylates tubulin along with other proteins involved in cell motility and traffics unfolded proteins for degradation through its ubiquitin-binding domain.

We aim to determine how the small molecule binds to HDAC6 using medicinal chemistry approaches and using a series of lead compounds with improved pharmacological properties, develop structure activity relationships. We aim to determine the molecular signalling events that occur after inhibition of HDAC6 to kill the chemoresistant cancer cells. We will also determine possible mechanisms of resistance to HDAC6 inhibition.

This drug discovery approach represents a paradigm shift to develop new therapeutics through pathways that are independent of mitochondrial apoptosis, ultimately addressing the lack of effective treatment options for refractory patients.