AUTHOR=Wang Yuting , He Mingyao , Li Xiang , Chai Jinlong , Jiang Qinglin , Peng Cheng , He Gu , Huang Wei 

TITLE=Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma

JOURNAL=Frontiers in Chemistry

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2021.700956

DOI=10.3389/fchem.2021.700956

ISSN=2296-2646

ABSTRACT=<p>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 <bold>4k</bold>–<bold>4r</bold> 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, <bold>4p</bold> displayed good inhibitory capacities on RalA (IC<sub>50</sub> = 0.22 μM) and HepG2 cells (IC<sub>50</sub> = 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.</p>