Seth Rose

Anticancer drug design: Seth Rose's research is aimed at development of anticancer drugs designed to combat drug resistance by cancer cells. A principal mode of resistance is by cells pumping the drugs out by use of efflux pumps e.g., p-glycoprotein. Since most anticancer agents are inhibitors that bind reversibly to enzymes, the drugs are removed from the target enzyme and lose their effectiveness. To combat this, Rose's research group is designing enzyme inhibitors that covalently bind to key cellular targets in cancer cells, such as the proteins involved in cell division. Thus, interference with the target proteins will be irreversible even when excess (unbound) drug is removed from the cancer cell. Such cells will fail to move through cell division due to cell cycle arrest and subsequently undergo apoptosis, the process of self-disassembly of the cell. Currently, they are investigating agents targeting microtubules, as well as cyclin-dependent kinases and protein tyrosine phosphatase beta.

The chemical strategy that they are currently employing makes use of electrophilic functional groups that react with nucleophilic groups in proteins. For example, nucleophiles react by conjugate addition to an alpha, beta-unsaturated pi system (C=C-C=O) incorporated into their compounds. The other part of the compound is used to confer specificity to the biological binding site. Other compounds they are investigating contain an epoxide group, the three-membered ring electrophilic ether. These compounds effectively induce apoptosis in human cancer cells grown in culture. They employ molecular modeling to examine the structures of the synthetic compounds docked to the target biomolecules, with the intent of enhancing binding efficiency and selectivity, as well as optimization of covalent reactivity. The group synthesizes and studies the reactivity of the new compounds toward model electrophiles, and with the help of collaborators, evaluate compounds for efficiency of cancer cell growth inhibition in human cancer cells, including multidrug-resistant cell lines, as well as determine the stage of cell cycle arrest and the efficiency of induction of apoptosis. This work may lead to new agents that overcome development of drug resistance by cancer cells.