Alghamdi Maha Alamodi, Deshpande Hemali
Department of Surgery, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Biotechnol Appl Biochem. 2025 Jan 7. doi: 10.1002/bab.2716.
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 IC 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 GI values of 490.70 and 615.14 nM, respectively. Moreover, SBL-027 induced an increase in the sub G/G 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.
双重抑制Akt和MEK1信号通路为提高胃癌治疗效果提供了一种有前景的策略。在本研究中，我们采用了计算方法并进行了体外验证。我们的结果表明，SBL - 027与Akt和MEK1激酶表现出强大而持久的相互作用，原子分子动力学模拟和基于分子力学泊松 - 玻尔兹曼表面积（MM - PBSA）的结合自由能估计证明了这一点。预测的吉布斯结合自由能表明SBL - 027与Akt和MEK1激酶之间存在高度有利的相互作用。在体外，SBL - 027对Akt的IC值为195.20 nM，对MEK1酶的IC值为239.10 nM。该化合物在KATOIII和SNU - 5细胞中表现出对细胞增殖的有效抑制，GI值分别为490.70和615.14 nM。此外，SBL - 027在KATOIII和SNU - 5细胞的细胞周期中诱导亚G / G期细胞群体增加，同时促进这些细胞系的早期和晚期凋亡。值得注意的是，该化合物显著降低了胃癌细胞中同时表达MEK1和Akt的双阳性细胞的百分比。SBL - 027强大的结合亲和力、稳定性和良好的热力学性质以及已确立的体外疗效突出了其作为进一步临床前和临床开发先导化合物的潜力。
