Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
Bioorg Chem. 2024 Oct;151:107682. doi: 10.1016/j.bioorg.2024.107682. Epub 2024 Aug 6.
c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI = 1.43 μM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC = 15 nM of c-MET) and STAT-3-IN-3 (IC = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.
c-MET 和 STAT-3 是癌症治疗的重要靶点。在这里，我们描述了一类非常有效的双重 STAT-3 和 c-MET 抑制剂，其骨架为基于香豆素的噻唑（3a-o）。光谱证据（NMR、HRMS 和 HPLC）验证了新化合物的结构发现。根据美国国家癌症研究所（NCI）的指导方针，还测试了这些化合物对一系列癌细胞的细胞毒性活性。化合物 3g 在 10 µM 时表现出活性，因此它被自动安排在五个剂量下进行测试。在 SNB-75（中枢神经系统癌细胞系）中，化合物 3g 显示出显著的体外抗癌活性，GI = 1.43 µM。对于分子靶标，与卡博替尼（c-MET 的 IC = 15 nM）和 STAT-3-IN-3（STAT-3 的 IC = 2.1 µM）相比，化合物 3g 对 STAT-3 和 c-MET 表现出很强的活性，IC 分别为 4.7 µM 和 12.67。此外，化合物 3g 显著诱导 SNB-75 细胞凋亡，导致凋亡细胞死亡增加 3.04 倍（处理细胞的总凋亡率为 11.53%，而参考细胞为 3.04%），坏死增加 3.58 倍。此外，它还使细胞停滞在 G2 期。使用 RT-PCR 进一步验证了 c-MET 和 STAT-3 蛋白激酶的双重抑制。通过应用分子对接确定了目标化合物的结合机制。
