Novel all-hydrocarbon stapled p110αE545K peptides as blockers of the oncogenic p110αE545K-IRS1 interaction

摘要

To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i+4]-stapled p110α[E545K] peptide >1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[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 % α-helicity than >1; moreover, the enhanced % α-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 p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study.