Imidazo[1,2-a]pyridine-based peptidomimetics as inhibitors of Akt

Abstract

We report the design, synthesis, and biological evaluation of imidazopyridine-based peptidomimetics based on the substrate consensus sequence of Akt, an AGC family serine/threonine kinase hyperactivated in over 50% of human tumors. Our ligand-based approach led to the identification of novel substrate mimetic inhibitors of Akt1 featuring an unnatural extended dipeptide surrogate. Compound 11 inhibits Akt isoforms in the sub-micromolar range and exhibits improved proteolytic stability relative to a parent pentapeptide.

Keywords: Dipeptide surrogate; Kinase inhibitor; Peptide mimic; β-Strand mimic.

Figure 1

Design of peptidomimetic Akt inhibitors

Figure 2

Phosphorylation of GSK3β fusion protein by Myc-tagged Akt1 immunoprecipitated from cell lysates.

Figure 3

In vitro inhibition of Akt isoforms by 11.

Figure 4

(A) Binding of compound 11 to Akt1 (pdb 1O6K) as determined by GLIDE XP docking. (B) Overlay of docked conformation of 11 (green) with the bound X-ray conformation of a substrate peptide (orange). Key interactions of 11 with Akt1 are shown.

Figure 5

Proteolytic degradation of 11 and a parent pentapeptide.

Scheme 1

Synthesis of imidazo[1,2-a]pyridine-based inhibitors.