科研之友
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摘要
The human epidermal growth factor receptor 2 (EGFR2 or HER2) has been established as a therapeutic target for HER2-positive breast cancer. Although a number of small-molecule agents have been developed to target HER2, many adverse drug reactions (ADRs) such as side effects and drug resistance are frequently observed in the chemotherapeutics. Previously, peptides derived from MIG6 protein, a natural negative regulator of EGFR and HER2, have been shown to destabilize EGFR dimerization (Zhang et al. 2007). Here, we grafted a MIG6 fragment ((336)KSLPSYLNGVMPPTQSFAPDPKYVSS(361)) in crystal interaction site from EGFR to HER2, truncated the fragment to obtain a short segment ((346)MPPTQSFA(353)) with reserved binding capability (K (d) = 121.6 +/- A 14.5 mu M) to HER2 kinase domain, and optimized the segment to improve its affinity for the domain. Consequently, three peptides (MLPNQSFA, MFPNQSFA and MFPYQSFA) were successfully designed to exhibit moderate or high potency (K (d) = 78.0 +/- A 9.8, 28.7 +/- A 3.9 and 65.1 +/- A 7.2 mu M, respectively) towards HER2 kinase domain, which are expected to destabilize HER2 dimerization and then suppress the kinase activation in breast cancer.
