Discovery of cloxiquine derivatives as potent HDAC inhibitors for the treatment of melanoma via activating PPARγ

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作   者：

Yang, Limin;  Ding, Ran;  Tong, Xiaojie;  Shen, Tong;  Jia, Shuting;  Yan, Xiqing;  Zhang, Chong;  Wu, Liqiang; 

作者机构：

Xinxiang Med Univ;  Jincheng Peoples Hosp; 

关键词：

Antimelanoma;  Cloxiquine;  PPAR gamma;  HDAC; 

期刊名称：

European Journal of Medicinal Chemistry

i s s n：

0223-5234

年卷期：

2025 年 281 卷

页   码：

117029-117029

页   码：

摘   要：

The combined treatment with histone deacetylase (HDAC) inhibitors with peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists has displayed significant anticancer efficacy. Based on these results, a series of cloxiquine derivatives were prepared as potent HDAC inhibitors for the treatment of melanoma. Among these compounds, CS4 exhibited excellent inhibitory effects on HDAC1 (IC50 = 38 nM) and HDAC6 (IC50 = 12 nM), and had good antiproliferative effects against A375 and SK-MEL-5 melanoma cells (IC50 values, 1.20 and 0.93 mu M, respectively). Mechanism research indicated that CS4 inhibited SK-MEL-5 cell growth by promoting alpha-tubulin and histone 3 (H3) acetylation. At the metabolic level, treatment with BG11 activated PPAR gamma and blocked glycolysis in SK-MEL-5 cells, which mediated partial antimelanoma effects of CS4. In addition, CS4 also induced cell cycle arrest at G2, suppressed migration and facilitated apoptosis of SK-MEL-5 cells. More importantly, compound CS4 demonstrated significant in vivo anticancer effect compared with SAHA, and exhibited neglectable toxicity. Consequently, CS4 is the potent HDAC inhibitor, which may be developed as the candidate antimelanoma drug.