SETH ROSE

Professor
Ph.D., University of California, San Diego, 1974

  Office: C-241  Lab: C-250, C-247, C-239
  Phone: (480)965-5459  
  Fax: (480) 965-2747
  Email: srose@asu.edu

Research and Teaching Interests

Anticancer drug design
Our 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, we are 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, we are investigating agents targeting microtubules, as well as cyclin-dependent kinases and protein tyrosine phosphatase beta.

The chemical strategy that we 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 our compounds. The other part of the compound is used to confer specificity to the biological binding site. Other compounds we are investigating contain an epoxide group, the three-membered ring electrophilic ether. These compounds effectively induce apoptosis in human cancer cells grown in culture. We 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. We synthesize and study 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.

Publications

"Anticancer agents based on prevention of protein prenylation," S. D. Rose, S. R. Ottersberg, K. J. Okolotowicz, D. E. Robinson, R. Hartman, and S. Lefler, U.S. Patent No. 7,344,851 (2008)

"Emollient, Humectant, and Fluorescent alpha,beta-Unsaturated Thiol Esters for Long-Acting Skin Applications," C. Robinson, R. F. Hartman and S. D. Rose, Bioorg. Chem. 36 265-270 (2008)

"Conjugated nitro alkene anticancer agents based on isoprenoid metabolism," S. D. Rose, K. J. Okolotowicz, R. F. Hartman, & J. Houtchens, U.S. Patent No. 7,312,191 (2007)

"Kinetics and Mechanism of the Addition of Nucleophiles to α,β-Unsaturated Thiol Esters," R. F. Hartman and S. D. Rose, J. Org. Chem. 71 6342−6350 (2006)

"Anticancer Agents Based on Regulation of Protein Prenylation," S. D. Rose, S. R. Lefler, S. R. Ottersberg, A. Y. Kim, K. J. Okolotowicz, and R. F. Hartman, U.S. Patent Number 7,019,031 (2006)