Optimal Se Incorporation in Small Molecules Drug Structures Elicits Enhanced Antitumor Activity

by

Professor Arun Sharma
Department of Molecular and Precision Medicine and the Director of the Organic Synthesis Shared Resource (OSSR) of the Penn State Cancer Institute (USA)

ABSTRACT: We have demonstrated that a rational incorporation of selenium (Se) atom into small molecule drug structures can significantly enhance anticancer activity, in many cases, however, being associated with increased systemic toxicity as well, which could be manipulated by appropriate structural modifications, lowering the dose owing to the enhanced potency, and/or incorporating the Se-compound into a nanoformulation. Over the years, we designed several Se-containing small molecules by incorporating Se into various natural products and drugs including temozolomide, NSAIDs, biotin, and kevetrin among others, and assessed their efficacy and toxicity using different preclinical cancer models. In most cases, the lead molecules from structure-activity relationship (SAR) studies of each series of Se analogs developed were 10-500-fold more potent than the parent compound/drug in inhibiting cancer cells’ growth, inducing apoptosis, and inhibiting xenograft tumor growth. I’ll present an overview of our research on developing potential organoselenium drug candidates. If time permits, I may also briefly highlight efforts to develop targeted therapeutic small molecules, including those following AI-driven drug design.