Hydrocarbon stapled peptides hold much promise as a general platform for inhibiting protein-protein interactions, but, beyond the initial reports, relatively little research has gone into exploring the amino acids used for this technology. Stapled peptides are typically designed to replace two non-interacting residues with the constraining, olefinic staple. In contrast to this approach, we recently reported a design strategy to leverage the lipophilic nature of the hydrocarbon staple by preparing new amino acids (λR and λS) that incorporate a methyl at the γ-position of the stapling amino acid S5. When incorporated into a peptide derived from steroid receptor coactivator-2 (SRC2), the resulting γ-methylated stapled peptides disrupt the estrogen receptor (ER) /SRC2 interaction with improved potency compared to the unsubstituted staple. In addition to inhibiting wildtype ER, these stapled peptides show good affinity to estrogen receptor mutants Y537S and D538G. ER-D538G and ER-Y537S have recently been reported to be highly prevalent mutations found in endocrine resistance breast cancer, however, the mechanistic role of these mutations has yet to be fully elucidated. Interestingly, the γ-methyl group of a stapled peptide we have previously prepared (SRC2-SP3) binds within 4 Å of estrogen receptor residue D538. Guided by x-ray crystallography and molecular dynamics studies, we have set out to prepare functionalized stapled peptides for selectively inhibiting ER-D538G. The selective inhibition of this ER isoform will shed new light on its involvement in the progression of breast cancer.

γ-Functionalized hydrocarbon stapled peptides for inhibiting mutant estrogen receptor/coactivator interaction

253rd National Meeting (2017)

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