Research Interests

Target Interactions of Camptothecin Anticancer Drugs with DNA and Topoisomerase I.
The camptothecin agents (CPT) are among the most promising new anticancer drugs, both in clinical use and experimental development. They are renowned for their unique mechanism of action- inhibition of DNA topoisomerase I (Topo I). Two camptothecins have recently been introduced into cancer clinics, with CPT-11 (Camptosar, Irinotecan) being used for colon cancer and topotecan (Hycamtin, TPT) being used for ovarian and lung cancers. Several other camptothecin derivatives are currently at various stages of clinical trials. Ongoing clinical trials indicate that camptothecin derivatives will be useful in a variety of other human cancers. However, camptothecin drugs still have problems with not being effective against certain types of cancer despite the associated elevated topoisomerase I level, and with the development of resistance by some cancer cells. Our research goal is to explore the molecular level details of the DNA-Topo I interactions of the camptothecins, and thence to obtain a better understanding of the mechanism of action accounting for their biological activities, which could ultimately lead to rational design of clinically more efficacious anticancer agents. High-field NMR spectroscopy and molecular computational modeling, in combination with molecular biology and biochemistry methods, are the primary approaches for this project.
Biologically Relevant DNA G-quadruplex Structures and Their Interactions with Potential Anticancer Compounds.
DNA G-quadruplex emerges as one of the most important new target for anticancer drug design. We are working on the structural analyses of the biologically relevant DNA G-quadruplexes, including telomeric DNA and c-myc oncogene promoter DNA, and their interactions with the G-quadruplex interacting compounds, which can be potentially developed as novel anticancer drugs.
Novel Topoisomerases Inhibitors and their Target Interactions.
Topoisomerase inhibitors constitute a major class of anticancer drugs and are among the most widely clinically used anticancer drugs for many types of cancers. There is a strong need for new, improved topoisomerase inhibitors. Dual inhibitors of topoisomerase I and II have been shown to have therapeutic advantages over single enzyme inhibitors, including sensitivity in resistant cells, more potent activity, and a broader spectrum of activity. For example, XR11576, a benzo-phenazine, and XR5944, a bis-phenazine, developed by the Xenova LTD (UK), are dual topo I/II inhibitors. Both drug compounds have entered Phase I clinical trials in Europe. Moreover, XR5944 has shown exceptional activity against human and murine tumor cells in vitro and in vivo. Our lab is working on the structural analysis of the DNA and protein interactions of the XR family of anticancer drugs, and of several other modified single topoisomerase I/or II inhibitors, for ultimate development of clinically more efficacious topoisomerase inhibitors.
  Platinum Anticancer Drug Interactions with DNA and Mechanisms of Action
 
  Essential Cellular Proteins as Drug Targets.
Structural studies of the cancer-related proteins, such as PRL-1; and the essential cellular proteins, such as phosphomevalonate kinase (PMK), and their interactions with potential inhibitors.