Design and Evaluation of Cyclized Small Peptides Derived from Her-2 as a Novel Therapeutic Strategy for Breast Cancer

摘要

Overexpression of Her-2 (HER2/neu/erbB-2) is found in 25-30% of human breast cancers and correlates with more aggressive tumors and a poorer prognosis. Therapies targeted at Her-2 have a great therapeutic potential for the treatment of breast cancers. The specific monoclonal antibody against Her-2, Herceptin (Trastuzumab), is currently an effective therapy for the treatment of human breast cancer with Her-2 overexpression. But Herceptin is effective in only about one third of breast cancers with Her-2 overexpression, indicating new strategies for targeting Her-2 are needed. In breast cancer cells with Her- 2 overexpression, abnormal cell proliferation is caused by the extremely high level of signal transduction, mediated by homodimerization of Her-2 and/or heterodimerization of Her-2 with EGFR, Her-3 and Her-4. Thus, agents that directly block the Her-2 dimerization may have a great therapeutic potential for treating Her-2 overexpressing breast cancer. The recently determined X-ray structures of Her-2 in complex with Herceptin and Her-2 show that Her-2 contains a hairpin loop an 'arm', protruding from the domain II. Importantly, a similar hairpin loop is also found in the X-ray structures of EGFR and Her-3. Based upon the critical structural information, we have designed, synthesized and evaluated-several cyclized small-molecule peptides as a new strategy to target the Her-2 protein by blocking its dimerization with members of EGFR receptors (EGFR, Her-2, and Her-3).