Special Organic Colloquium – Prof. Stuart Conway

“The development and targeting of epigenetic drugs for therapeutic benefit”

Abstract: The talk will comprise two interconnected parts describing the development and targeting of epigenetic drugs for the treatment of disease. 

The development of bromodomain ligands for the treatment of disease: bromodomains, protein modules that ‘read’ of lysine acetylation state, have emerged as important therapeutic targets for indications including oncology. I will describe our work on the design and synthesis of inhibitors for the BET and CREBBP/EP300 bromodomains, their biological effects, and their role as leads for cancer drug discovery. While the function of some human bromodomain-containing proteins (BCPs) has been heavily investigated, little is known about the role of these proteins in other species. I will describe work to identify 22 BCPs in Schistosoma mansoni (schistosomiasis/bilharzia). We have annotated one of these proteins as SmBRD3, in analogy to human BRD3, a member of the BET bromodomain family. I will discuss the design, synthesis, and validation of high affinity ligands for SmBRD3 and the use of these ligands in phenotypic studies on S. mansoni. 

Targeting and imaging tumour hypoxia: Tumor hypoxia (low oxygen) is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, which target oxygen-deficient cells, represent a promising treatment strategy. We have demonstrated the pre-clinical efficacy of NI-Pano, a novel hypoxia-activated pro-drug of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano is stable in normoxic (21% oxygen) conditions and undergoes NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% oxygen). NI-Pano exhibited growth delay effects as a single agent in mouse tumor xenografts. Pharmacokinetic analysis confirmed the presence of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Our preclinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors. Work to develop complementary imaging agents for hypoxia will also be discussed.