Wang Yuting, He Mingyao, Li Xiang, Chai Jinlong, Jiang Qinglin, Peng Cheng, He Gu, Huang Wei
State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
State Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University, Chengdu, China.
Front Chem. 2021 Nov 15;9:700956. doi: 10.3389/fchem.2021.700956. eCollection 2021.
The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds - suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, displayed good inhibitory capacities on RalA (IC = 0.22 μM) and HepG2 cells (IC = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.
包括RalA和RalB在内的Ras小GTP酶的激活在致癌、肿瘤进展和转移中起重要作用。在本研究中，我们报告发现了一系列6-磺酰胺基-吡喃并[2,3-c]吡唑衍生物作为新型RalA抑制剂。基于酶联免疫吸附测定（ELISA）的生化分析结果表明，这些化合物抑制了RalA/B与其底物的结合能力。细胞增殖试验表明，这些RalA抑制剂能有效抑制肝癌细胞系的增殖，包括HepG2、SMMC-7721、Hep3B和Huh-7细胞。在所评估的化合物中，[具体化合物]对RalA（IC = 0.22 μM）和HepG2细胞（IC = 2.28 μM）表现出良好的抑制能力。总体而言，我们的结果表明，一种具有6-磺酰胺基-吡喃并[2,3-c]吡唑支架的新型小分子RalA抑制剂可抑制肝癌中的自噬和细胞增殖，并且具有肝癌靶向治疗的潜力。
