Department of General Surgery, Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310016, China.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Comb Chem High Throughput Screen. 2023;26(7):1364-1374. doi: 10.2174/1386207325666220830145026.
Sorafenib is the most widely used systematic therapy drug for treating unresectable Hepatocellular Carcinoma (HCC) but showed dissatisfactory efficacy in clinical applications.
We conducted a combinational quantitative small-molecule high-throughput screening (qHTS) to identify potential candidates to enhance the treatment effectiveness of sorafenib.
First, using a Hep3B human HCC cell line, 7051 approved drugs and bioactive compounds were screened, then the primary hits were tested with/without 0.5 μM sorafenib respectively, the compound has the half maximal Inhibitory Concentration (IC50) shift value greater than 1.5 was thought to have the synergistic effect with sorafenib. Furthermore, the MEK inhibitor PD198306 was selected for the further mechanistic study.
12 effective compounds were identified, including kinase inhibitors targeting MEK, AURKB, CAMK, ROCK2, BRAF, PI3K, AKT and EGFR, and a μ-opioid receptor agonist and a Ltype calcium channel blocker. The mechanistic research of the combination of sorafenib plus PD198306 showed that the two compounds synergistically inhibited MEK-ERK and mTORC1- 4EBP1 and induced apoptosis in HCC cells, which can be attributed to the transcriptional and posttranslational regulation of MCL-1 and BIM.
Small-molecule qHTS identifies MEK inhibitor PD1938306 as a potent sorafenib enhancer, together with several novel combination strategies that are valuable for further studies.
索拉非尼是治疗不可切除肝细胞癌（HCC）最广泛使用的系统治疗药物，但在临床应用中疗效并不理想。
我们进行了组合定量小分子高通量筛选（qHTS），以确定潜在的候选药物来增强索拉非尼的治疗效果。
首先，我们使用 Hep3B 人 HCC 细胞系筛选了 7051 种已批准的药物和生物活性化合物，然后分别用/不用 0.5 μM 索拉非尼测试初级命中化合物，IC50 变化值大于 1.5 的化合物被认为与索拉非尼具有协同作用。此外，选择 MEK 抑制剂 PD198306 进行进一步的机制研究。
鉴定出 12 种有效化合物，包括针对 MEK、AURKB、CAMK、ROCK2、BRAF、PI3K、AKT 和 EGFR 的激酶抑制剂，以及一种μ-阿片受体激动剂和一种 L 型钙通道阻滞剂。索拉非尼加 PD198306 联合用药的机制研究表明，两种化合物协同抑制 MEK-ERK 和 mTORC1-4EBP1，并诱导 HCC 细胞凋亡，这归因于 MCL-1 和 BIM 的转录和翻译后调节。
小分子 qHTS 鉴定出 MEK 抑制剂 PD1938306 是一种有效的索拉非尼增强剂，与几种新的联合策略一起，对进一步研究具有重要价值。
