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

WT Scheme: Seed Award in Science

The majority of cytotoxic agents used to treat patients kill tumour cells via the mitochondrial pathway of cell death. Previously, the applicant found that primary tumours that are chemoresistant in vivo usually contain mitochondria that are resistant to apoptotic signalling. Therefore, we performed a small molecule screen to identify new therapeutic small molecules that can preferentially kill cancer cells independent of mitochondrial apoptosis. To our knowledge, we identified the first reported case of a specific HDAC6 inhibitor. HDAC6 is a highly interesting protein as it deacetylates tubulin along with other proteins involved in cell motility and through its ubiquitin binding domain traffics unfolded proteins for degradation. Using medicinal chemistry approaches we aim to determine how the small molecule discovered binds to HDAC6 and using structure activity relationships develop a series of lead compounds with improved pharmacological properties. We aim to determine the molecular signalling events that occur following inhibition of HDAC6 to kill the chemoresistant cancer cells. Lastly, we aim to 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.

Award Date
01 June 2016
Award Value
€127,136
Principal Investigator
Professor Triona Ni Chonghaile
Host Institution
Royal College of Surgeons in Ireland
Scheme
SFI-HRB-Wellcome Research Partnership