EDWARD SKIBO

Professor
Ph.D., University of California, San Francisco, 1980

  Office: C-302  Lab: C-338/334
  Phone: (480)965-3581  Lab Phone: (480)965-8586
  Fax: (480) 965-2747
  Email: eskibo@asu.edu

 EDWARD SKIBO's Lab Website

Research and Teaching Interests

Ongoing research in this laboratory has been involved with the study of DNA cleaving agents based on quinone methides, cyclopropyl quinone methides, activated aziridines, iminium ions and ene-imines. In addition, computer models are used to develop inhibitors of heat shock protein Hsp90, topoisomerase II, and the key enzyme in purine de novo synthesis IMP dehydrogenase. The goal of this research program is to develop novel antitumor agents displaying high cancer specificity.

Activated aziridines include the pyrrolobenzimidazoles (PBIs) and indole-based ene-imine DNA cross-linkers that are capable of causing hydrolytic cleavage of the DNA phosphate backbone at precise locations. By tethering these cutting species to amino acids and peptides in different ways it is possible to influence the site of DNA cleavage as well as the histologic cancer specificity. The cyclopentyl[b]indole quinone methides are a new class of DNA neutral intercalating / alkylating agent able to recognize DNA base pairs. This reactive species builds up and persists in solution and thus possesses in vivo activity.

New intercalating catalytic inhibitors of topoisomerase II are under development based on benzimidazole topoisomerase II catalytic inhibitors, called APBIs, as well as on analogues of makaluvamine and wakayin indole natural products. The aim is to design a topoisomerase II catalytic inhibitor structure that inhibits the “closed clamp” catalytic intermediate. Heat shock protein (Hsp90) is a relatively new target for cancer chemotherpy and has been the subject of intense drug design efforts. The approach to Hsp-90 inhibitor design is to use molecular modeling into the protein’s N-terminal domain to develop lead analogues. Structurally simple quinolinedione, resorcinol, and the quinazoline analogues have been designed from the Hsp-90 crystal structure. Finally non-nucleotide inhibitors of the purine de novo synthetic enzyme IMP-dehydrogenase have been designed using computer modeling. These new inhibitors are designed to be bio-available in contrast to nucleotide and nucleoside inhibitors.

Representative Publications

"Pyrrolobenzimidazoles (PBIs) Linked to Heterocycles and Peptides. Design of DNA Base Pair Specific Phosphate Hydrolyzing Agents and Novel Cytotoxic Agents," A. Ghodousi, X. Huang, Z. Cheng and E.B. Skibo, J Med Chem 47, 90-100 (2004).

"Design of Quinolinedione-Based Geldanamycin Analogues," R. Hargreaves, C.L. David, L. Whitesell and E.B. Skibo, Bioorg. Med. Chem. Lett. 13, 3075-3078 (2003).

"Insights into the Mechanism and Substrate Specificty of Human DT-Diaphorase through Molecular Modeling," A. Suleman and E.B. Skibo, J Med Chem 45, 1211-1220 (2002).

"Aziridinyl Quinone Antitumor Agents based on Indoles and Cyclopent[b]indoles: Structure Activity Relationships for Cytotoxicity and Antitumor Activity," C. Xing, E.B. Skibo and R.T. Dorr, J Med Chem 44, 3545-3562 (2001).

"Recognition and Cleavage at the DNA Major Groove," E.B. Skibo, C. Xing and T. Groy, Bioorg. Med. Chem 9, 2445-2459 (2001).