Al Shahrani Mesfer, Abohassan Mohammad, Alshahrani Mohammad, Gahtani Reem M, Rajagopalan Prasanna
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
Biochem Biophys Res Commun. 2025 Feb;746:151225. doi: 10.1016/j.bbrc.2024.151225. Epub 2025 Jan 2.
Transforming growth factor-beta (TGF-β) plays a pivotal role in breast development by modulating tissue composition during the developmental phase. The TGFβ type II receptor (TGFβ RII) is implicated in breast cancer and represents a valuable therapeutic target. Due to the off-target side effects of many existing TGFβI/TGFβ RII inhibitors, a more targeted approach to drug discovery is necessary. This study used computational modeling and molecular dynamics simulations to screen the ChemBridge small molecule library against TGFβ RII.
This study employed high-throughput virtual screening, molecular dynamics simulations, and binding free energy calculations to identify potential inhibitors targeting TGF-β RII. MDA-MB 231 and MCF-7 breast cancer cells were used in anti-proliferative, tans-endothelial migration, and flow cytometric assays for in vitro validations.
We identified 8-(2-methylphenyl)-9H-benzo[f]indeno[2,1-c]quinolin-9-one (C-5635020) as a potent and selective inhibitor. Protein-ligand modeling analysis revealed that C-5635020 targets the kinase domain of TGFβ RII with superior binding affinities compared to the standard drug, staurosporine. Computational results suggest that C-5635020 selectively binds and inhibits TGFβ RII activity, thereby controlling cell proliferation in breast cancer. In vitro, experiments corroborated these predictions, where C-5635020 inhibited TGFβ RII and p-Smad 2/3 positive population in MDAMB-231 and MCF-7 cells. The compound dose-dependently inhibited cell proliferation, trans-endothelial migration, and increased apoptosis in both breast cancer cell lines.
The strong binding affinity, stability, and favorable thermodynamics of C-5635020 with established in vitro efficacy highlight its potential as a lead compound for further preclinical and clinical developments for breast cancer treatment.
转化生长因子-β（TGF-β）在乳腺发育阶段通过调节组织组成发挥关键作用。TGFβ II型受体（TGFβ RII）与乳腺癌有关，是一个有价值的治疗靶点。由于许多现有TGFβI/TGFβ RII抑制剂存在脱靶副作用，因此需要一种更具针对性的药物研发方法。本研究利用计算建模和分子动力学模拟对ChemBridge小分子文库进行针对TGFβ RII的筛选。
本研究采用高通量虚拟筛选、分子动力学模拟和结合自由能计算来鉴定针对TGF-β RII的潜在抑制剂。使用MDA-MB 231和MCF-7乳腺癌细胞进行抗增殖、跨内皮迁移和流式细胞术分析以进行体外验证。
我们鉴定出8-（2-甲基苯基）-9H-苯并[f]茚并[2,1-c]喹啉-9-酮（C-5635020）为一种强效且选择性的抑制剂。蛋白质-配体建模分析表明，与标准药物星形孢菌素相比，C-5635020以更高的结合亲和力靶向TGFβ RII的激酶结构域。计算结果表明，C-5635020选择性结合并抑制TGFβ RII活性，从而控制乳腺癌细胞的增殖。在体外，实验证实了这些预测，其中C-5635020抑制了MDAMB-231和MCF-7细胞中的TGFβ RII和p-Smad 2/3阳性群体。该化合物在两种乳腺癌细胞系中均剂量依赖性地抑制细胞增殖、跨内皮迁移并增加细胞凋亡。
C-5635020具有强结合亲和力、稳定性以及良好的体外疗效，突出了其作为乳腺癌治疗进一步临床前和临床开发先导化合物的潜力。
