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.