A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery

Abstract

mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with IC 50 values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 (GI 50 = 4.66 μM) and HCT116 (GI 50 = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-ofprinciple study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor.

Computational targeting of allosteric site of MEK1 by quinoline‐based molecules

“…Therefore, to identify potential MEK1 inhibitors with good efficacy, molecular docking, long‐term molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA) studies were implemented. Previous studies as well as the patents have claimed several quinoline derivatives as a prosperous scaffold for cancer and a noncompetitive inhibitor of MEK1 18–23 . In this study, we have selected 37 in‐house quinoline derivatives to discover allosteric inhibitors of MEK1 in comparison with four reference molecules (three identified inhibitors and one cocrystal) 24 …”

“…Previous studies as well as the patents have claimed several quinoline derivatives as a prosperous scaffold for cancer and a noncompetitive inhibitor of MEK1. [18][19][20][21][22][23] In this study, we have selected 37 in-house quinoline derivatives to discover allosteric inhibitors of MEK1 in comparison with four reference molecules (three identified inhibitors and one cocrystal). 24 2 | COMPUTATIONAL METHODOLOGY…”