Novel all-hydrocarbon stapled p110?[E545K] peptides as blockers of the oncogenic p110?[E545K]-IRS1 interaction.

ABSTRACT: To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i?+?4]-stapled p110?[E545K] peptide 1?that was shown to potently block the intracellular p110?[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110?[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, 4-A, and 4-B had higher % ?-helicity than 1; moreover, the enhanced % ?-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?[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110?[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110?[E545K] peptides newly identified in the current study.

SUBMITTER: Hu X 

PROVIDER: S-EPMC5711480 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature