Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3‑Kinase (PI3K)

The
synthesis of a series of single entity, bifunctional MEK1/PI3K
inhibitors achieved by covalent linking of structural analogs of the
ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive
MEK inhibitor PD0325901 is described. Inhibitors displayed potent
in vitro inhibition of MEK1 (0.015 < IC50 (nM) <
56.7) and PI3K (54 < IC50 (nM) < 341) in enzymatic
inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated
with inhibitors 9 and 14 in two tumor cell
lines (A549, D54). Inhibitors produced dose-dependent decreased cell
viability similar to the combined administration of equivalent doses
of ZSTK474 and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated
in D54 glioma and A549 lung tumor bearing mice. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation,
respectively, at 2 h postadministration by Western blot analysis,
confirming the bioavailability and efficacy of this bifunctional inhibitor
strategy toward combined MEK1/PI3K inhibition.