The major focus of Dr. Arun Sharma’s lab is the design and development of novel small drug-like molecules as potential cancer therapeutic and preventive agents, and testing them in various in vitro and in vivo cancer models.

This effort has resulted in the development of some potent anti-cancer agents and understanding of their efficacy, toxicity, pharmacokinetics, and mechanisms of action. The main strategies adapted for designing new agents include optimization of

• naturally occurring agents;
• existing drugs or agents that fail in clinical trials; and
• lead compounds obtained from chemical library screening, to enhance potency, bioavailability and therapeutic/chemopreventive index.

An example of natural product optimization includes the development of ISC-4, an isosteric selenium analog of isothiocyanates that occur naturally in cruciferous vegetables. ISC-4 was shown to be a PI3K/Akt pathway inhibitor that effectively inhibited tumor growth in melanoma and colon cancer xenograft models, alone and in combination with standard of care. Further optimization of ISC-4 structure has now led to a dual Akt pathway/topoisomerase II inhibitor NISC-6 as a potential melanoma therapeutic.

Through extensive structure-activity studies based on Selenium-NSAID hybrid molecules, Dr. Sharma’s lab has recently discovered two potent small molecules: Se-Aspirin, published recently and already commercially available; and AS-10, a bis-aspirinyl-selenazolidine analog which has shown great potential as a cancer therapeutic, particularly for pancreatic cancer. p-XS-Asp, another Se-aspirin hybrid molecule developed recently, is orally bioavailable and effective in preventing against NNK induced lung tumorigenesis.

Apart from developing anti-cancer compounds, Dr. Sharma’s lab is also focusing on developing "smart antibiotics." The emphasis is on designing and synthesizing cationic bolaamphiphiles (CABs) as carrier compounds that can transport antisense oligonucleotide (ASO) into C. difficile to selectively target the genetic material in C. difficile.