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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Hu, Xiao¹  He, Yanhua¹  Wu, Liping^2,3  Hao, Yujun^2,3  Wang, Zhenghe^2,3  Zheng, Weiping¹ 

[1] Jiangsu Univ, Sch Pharm, 301 Xuefu Rd, Zhenjiang 212013, Jiangsu, Peoples R China

[2] Case Western Reserve Univ, Dept Genet & Genome Sci, 10900 Euclid Ave, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Case Comprehens Canc Ctr, 10900 Euclid Ave, Cleveland, OH 44106 USA

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

DOI  :  10.1016/j.bmcl.2017.10.076

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free