Dual Targeting of MEK1 and Akt Kinase Identified SBL-027 as a Promising Lead Candidate to Control Cell Proliferations in Gastric Cancer.

Abstract

Dual inhibition of Akt and MEK1 pathways offers a promising strategy to enhance treatment efficacy in gastric cancer. In this study, we employed computational approaches followed by in vitro validations. Our results demonstrate that SBL-027 exhibits robust and enduring interactions with Akt and MEK1 kinases, as evidenced by atomistic molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) based binding free energy estimates. The predicted Gibbs binding free energies indicate highly favorable interactions between SBL-027 and both Akt and MEK1 kinases. In vitro, SBL-027 displayed an IC₅₀ value of 195.20 nM against Akt and 239.10 nM against MEK1 enzymes. The compound exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells, with GI₅₀ values of 490.70 and 615.14 nM, respectively. Moreover, SBL-027 induced an increase in the sub G₀/G₁ population during the cell cycle of KATOIII and SNU-5 cells, while facilitating early and late-phase apoptosis in these cell lines. Notably, the compound significantly reduced the percentage of dual-positive cells expressing both MEK1 and Akt in gastric cancer cells. The strong binding affinity, stability, and favorable thermodynamics of SBL-027 along with the established in vitro efficacy highlight its potential as a lead compound for further preclinical and clinical development.