Novel all-hydrocarbon stapled p110α[E545K] peptides as blockers of the oncogenic p110α[E545K]-IRS1 interaction

作者：Hu, Xiao; He, Yanhua; Wu, Liping; Hao, Yujun; Wang, Zhenghe; Zheng, Weiping^*

来源：Bioorganic & Medicinal Chemistry Letters, 2017, 27(24): 5446-5449.

DOI：10.1016/j.bmcl.2017.10.076

• Protein-protein interaction
• p110 alpha[E545K]
• IRS1
• Stapled peptide
• % alpha-helicity
• Proteolytic stability
• AKT phosphorylation
• Anti-cancer therapeutic

To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110 alpha[E545K] peptide 1 that was shown to potently block the intracellular p110 alpha[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110 alpha[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4A, and 4-B had higher % alpha-helicity than 1; moreover, the enhanced % alpha-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110 alpha[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110 alpha[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110 alpha[E545K] peptides newly identified in the current study.

• 出版日期2017-12-15
• 单位江苏大学