“ Small Molecules for Understanding Life & Managing Disease ”

Histone deacetylase (HDAC) inhibition is a clinically validated cancer treatment strategy which targets the components of the cellular epigenetic machinery. Despite promises in preclinical studies, HDAC inhibitors (HDACi) have been less efficacious in treating solid tumors. To address this problem, we envisioned the design of HDACi equipped with secondary pharmacophores to facilitate selective accumulation in malignant cells and diseased tissues. In this presentation, I will highlight representative examples of targeted HDACi that we have discovered and subsequently discuss the design, structure activity relationship studies and in vivo efficacy of new class of HDACi which target the prostate tumors via interaction with androgen receptor (AR). I will present data showing that the potency of a subset of these compounds is enhanced with increase in the expression levels of AR. Potentially, these compounds are rare examples of agents whose potency is anticipated to be enhanced with increase in the expression of a driver of drug resistance phenotype. Acknowledgement: This work was supported by the U.S. National Institutes of Health (Grant # R01CA131217, R21CA185690 and R43CA180508) and the Georgia Research Alliance (Grant # GRA.VL13.B11.)