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<p>The pyrazolopyridine scaffold exhibits excellent antitumor activity and has aroused public attention because of its high efficiency, low toxicity and unique mode of action. In this paper, six pyrazolopyridine analogs <b>E1</b>-<b>E6</b> were preliminarily designed via scaffold shopping and synthesized economically. Compound <b>E5</b> (IC<sub>50</sub> = 9.41 μM) was found to be the most potent analog and showed better antiproliferative ability than sorafenib (IC<sub>50</sub> = 10.06 μM) against the HepG2 cell by MTT assay. The results of the wound healing and transwell migration assays indicated that <b>E5</b> had strong potential for suppressing HepG2 cell migration in a dose- and time-dependent manner. Subsequent assays, including JC-1 staining, Bcl-2 and caspase 3 protein levels via western blotting, confirmed that <b>E5</b> exposure could promote apoptosis in HepG2 cells. The underlying mechanism of its cytotoxicity was also investigated and the western blotting results confirmed that <b>E5</b> exposure inhibited the CXCR2/RAF/ERK pathway and MMP2 expression. Molecular docking further supported that <b>E5</b> showed a high affinity to the CXCR2 protein. The results favored our rational design intention and hinted that the new pyrazolopyridines might be helpful in the further exploration of potent agents.</p>

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Discovery of Novel Pyrazolopyridine Analogs as Potential Anti-Hepatoma Agents by Suppressing the CXCR2/RAF/ERK Pathway

  • 期刊论文

  • 发表日期：

    2025年6月1日

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  • Weiya Cao,
  • Pan Yu,
  • Qizhu Feng,
  • Shuhui Feng,
  • Shilong Yang

摘要

The pyrazolopyridine scaffold exhibits excellent antitumor activity and has aroused public attention because of its high efficiency, low toxicity and unique mode of action. In this paper, six pyrazolopyridine analogs E1-E6 were preliminarily designed via scaffold shopping and synthesized economically. Compound E5 (IC50 = 9.41 μM) was found to be the most potent analog and showed better antiproliferative ability than sorafenib (IC50 = 10.06 μM) against the HepG2 cell by MTT assay. The results of the wound healing and transwell migration assays indicated that E5 had strong potential for suppressing HepG2 cell migration in a dose- and time-dependent manner. Subsequent assays, including JC-1 staining, Bcl-2 and caspase 3 protein levels via western blotting, confirmed that E5 exposure could promote apoptosis in HepG2 cells. The underlying mechanism of its cytotoxicity was also investigated and the western blotting results confirmed that E5 exposure inhibited the CXCR2/RAF/ERK pathway and MMP2 expression. Molecular docking further supported that E5 showed a high affinity to the CXCR2 protein. The results favored our rational design intention and hinted that the new pyrazolopyridines might be helpful in the further exploration of potent agents.