Otifi Hassan M
Department of Pathology, College of Medicine, King Khalid University, Abha, 62521, Saudi Arabia.
Oncol Res. 2024 Dec 20;33(1):235-243. doi: 10.32604/or.2024.055677. eCollection 2025.
Gastric cancer (GC) remains a global health burden and is often characterized by heterogeneous molecular profiles and resistance to conventional therapies. The phosphoinositide 3-kinase and PI3K and Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathways play pivotal roles in GC progression, making them attractive targets for therapeutic interventions.
This study applied a computational and molecular dynamics simulation approach to identify and characterize SBL-JP-0004 as a potential dual inhibitor of JAK2 and PI3KCD kinases. KATOIII and SNU-5 GC cells were used for evaluation.
SBL-JP-0004 exhibited a robust binding affinity for JAK2 and PI3KCD kinases, as evidenced by molecular docking scores and molecular dynamics simulations. Binding interactions and Gibbs binding free energy estimates confirmed stable and favorable interactions with target proteins. SBL-JP-0004 displayed an half-maximal inhibitory concentration (IC) value of 118.9 nM against JAK2 kinase and 200.9 nM against PI3KCD enzymes. SBL-JP-0004 exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells, with half-maximal growth inhibitory concentration (GI) values of 250.8 and 516.3 nM, respectively. A significant elevation in the early phase apoptosis (28.53% in KATOIII cells and 26.85% in SNU-5 cells) and late phase apoptosis (17.37% in KATOIII cells and 10.05% in SNU-5 cells) were observed with SBL-JP-0004 treatment compared to 2.1% and 2.83% in their respective controls.
The results highlight SBL-JP-0004 as a promising dual inhibitor targeting JAK2 and PI3KCD kinases for treating GC and warrant further preclinical and clinical investigations to validate its utility in clinical settings.
胃癌（GC）仍然是一项全球健康负担，其特征通常是分子谱异质性以及对传统疗法产生耐药性。磷酸肌醇3-激酶（PI3K）和Janus激酶（JAK）信号转导子和转录激活子（JAK-STAT）通路在胃癌进展中起关键作用，使其成为治疗干预的有吸引力的靶点。
本研究应用计算和分子动力学模拟方法来鉴定和表征SBL-JP-0004作为JAK2和PI3KCD激酶的潜在双重抑制剂。使用KATOIII和SNU-5胃癌细胞进行评估。
分子对接分数和分子动力学模拟表明，SBL-JP-0004对JAK2和PI3KCD激酶表现出强大的结合亲和力。结合相互作用和吉布斯结合自由能估计证实了与靶蛋白的稳定且有利的相互作用。SBL-JP-0004对JAK2激酶的半数最大抑制浓度（IC）值为118.9 nM，对PI3KCD酶的IC值为200.9 nM。SBL-JP-0004在KATOIII和SNU-5细胞中表现出对细胞增殖的有效抑制，其半数最大生长抑制浓度（GI）值分别为250.8和516.3 nM。与各自对照组的2.1%和2.83%相比，SBL-JP-0004处理后观察到早期凋亡（KATOIII细胞中为28.53%，SNU-5细胞中为26.85%）和晚期凋亡（KATOIII细胞中为17.37%，SNU-5细胞中为10.05%）显著升高。
结果突出了SBL-JP-0004作为一种有前景的双重抑制剂，靶向JAK2和PI3KCD激酶用于治疗胃癌，值得进一步进行临床前和临床研究以验证其在临床环境中的效用。
