Synergistic Inhibition of Her2/neu and p53-MDM2 Pathways. Addendum

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) 01-09-2007 REPORT TYPE Addendum to Final DATES COVERED (From -To AUTHOR(S)Nouri Neamati, Ph.D.5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: neamati@usc.edu 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUniversity of Southern California Los Angeles, CA 90033 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTOverexpression of HER2/neu, as well as the overexpression of MDM2 has been known to be significant markers in malignancy of breast cancer in different ways. Activating the p53 pathway (a tumor suppressor protein) by inhibiting MDM2 activity while inactivating HER2/neu (a tumor activating protein) is a unique strategy to restore both wild type p53 function and inhibit poor breast cancer cell receptor function. Therefore, combination of drugs targeting HER2/neu and MDM2 pathways will allow for a two-pronged attack on breast cancer. The overall objective of our proposal is to determine if small molecule drugs designed to inhibit HER2/neu can be applied in combination with drugs designed to inhibit p53-MDM2 activity. This will enable us to ascertain if there is a synergistic effect as well as allow us to develop an understanding of the critical players in the overall cell signaling cascade. Initially, our objectives will be to design novel therapeutic agents based on pharmacophore and docking studies able to inhibit either the HER2/neu pathway or the p53-MDM2 pathway. Subsequently, designed small molecule drugs able to strongly induce apoptosis in breast cancer cell lines by inhibiting either pathway will be used in combination studies in vitro and in vivo to assess synergistic effects. Shape-merged single compound pharmacophore query. Catalyst software package was used to generate the explicit shape constraint of Nutlin or p53 side chain ligand (Figures 1 and 2...