SUBSTRATE-MIMETIC AKT INHIBITOR

摘要

Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.

主权项

1. A method of inhibiting AKT in at least one cell, comprising contacting a cell with a composition, wherein the composition comprises the formula:
Y1-Y2—X1—Y3—F—X2  (I); wherein Y1 is acetyl, G-A-P-, acetylated G-A-P, G-R-P, or acetylated G-R-P-; wherein Y2 is R or A;
where Y2 is A when Y1 is G-R-P or acetylated G-R-P; wherein X1 is -T-T-, where X3 is N-benzyl acetamide;where X4 is hydrogen, methyl, or phenyl;where X5 is hydrogen, phenyl, or napthyl; wherein Y3 is S or V; wherein X2 is aminobenzyl, benzyl, wherein G is glycine, R is arginine, P is proline, T is threonine, W is tryptophan, F is phenylalanine, H is histidine, V is valine, A is alanine, C is cysteine, and N is asparagine.