Discovery of Potent Inhibitors for Breast Cancer Multidrug Resistance [report]

Geoffrey Chang, M. G. Finn, Ina Urbatsch
2006 unpublished
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more » ... torate 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. regimens. Although the precise nature of this clinical phenomenon is unclear and is likely due to several factors, the majority of breast tumors, like several other cancers, acquire resistance by multidrug efflux pumps. Several inhibitors (like Novartis compound PSC833) have already been discovered targeting both human MDR transporters. These MDR reversing agents however have been lacking in their potencies and their mechanism of action has been unknown. We have applied a highly integrated and innovative approach for the discovery of potent MDR inhibitors of breast cancer MDR by combining the most cutting-edge methods in chemical synthesis, drug discovery, and molecular structure. We have implemented click chemistry to produce a library of inhibitors, (2) developed functional assays, and (3) determined the structure of a close ortholog of hMDR1 with these anti-cancer compounds. SUBJECT TERMS Multidrug Resistance, Structure, transporters, click chemistry, functional assays 16. SECURITY CLASSIFICATION OF: 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 26 19b. TELEPHONE NUMBER (include area code) Standard Form 298 (Rev. 8-98)
doi:10.21236/ada452780 fatcat:n3d4k5ulhjdqlb4cbj5yehdvxe