HIF-1α SUMOylation Inhibitor

Suppresses tumor growth

Small molecule XZA-1 activates HADH, increasing intracellular acetoacetyl-CoA levels, which promotes acetoacetylation of CBX4 at K106, thereby inhibiting its SUMO E3 ligase activity and reducing HIF-1α transcriptional activation, showing antitumor effects in a CBX4-overexpressing xenograft model.

Li, Huiti · Xu, Ying · Zheng, Yimin · Zian, Xue · Jiang, Lulu · Ruan, Xiaoxue · Zhang, Rong · Yin, Yue · Fuyuan, Li · Huang, He · Jin, Li · Tan, Minjia · Fan, Jia · Cai, Jiabin · Chen, Guoqiang · Zhou, Lu

Cell Chemical Biology 2025

Specifications

Compound library size

{'zh': '101,254', 'en': '101,254'}

Advantages

Activates endogenous metabolism to generate an antitumor metabolite

XZA-1 activates HADH to increase intracellular acetoacetyl-CoA, which promotes CBX4 K106 acetoacetylation and inhibits its SUMO E3 ligase activity, thereby reducing HIF-1α transcriptional activation.

Shows antitumor effects in an animal model

In a CBX4-overexpressing xenograft model, XZA-1 demonstrated antitumor effects by enhancing CBX4 K106 acetoacetylation, validating the mechanism in vivo.

Correlates with better clinical prognosis

Elevated CBX4 K106 acetoacetylation in clinical HCC tissues correlated with better overall survival, suggesting the modification may serve as a prognostic marker.

Applications

• Antitumor small molecule：Serve as a lead antitumor candidate for preclinical efficacy evaluation.
• HIF-1α pathway inhibitor：Used to study the role of the HIF-1α pathway in cancer and its pharmacological intervention.
• SUMOylation modulator：Serve as a tool compound to modulate CBX4 SUMO E3 ligase activity.
• HCC therapy：For targeted therapy development and prognostic marker research in hepatocellular carcinoma.