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

The combined treatment with histone deacetylase (HDAC) inhibitors with peroxisome proliferator-activated receptor γ (PPARγ) 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 μM, respectively). Mechanism research indicated that CS4 inhibited SK-MEL-5 cell growth by promoting α-tubulin and histone 3 (H3) acetylation. At the metabolic level, treatment with BG11 activated PPARγ 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.