A Novel CSN5 Inhibitor Drives Tumor-Intrinsic PD-L1 Degradation and Exerts Direct Antitumor Efficacy in Triple-Negative Breast Cancer

Targeting the oncoprotein CSN5 represents a promising therapeutic strategy for triple-negative breast cancer (TNBC), given its critical role in stabilizing PD-L1 and promoting tumor progression. Here, we developed a novel series of <i>4-NH</i>-substituted azaindole derivatives as potent CSN5 inhibitors. Among them, through systematic structural modifications and SAR analysis at key positions, we identified <b>30</b> as a potent candidate with an IC₅₀ of 0.58 μM. This compound effectively inhibited CSN5 activity, promoted NEDD8-Cul1 accumulation, and triggered tumor cell-autonomous PD-L1 degradation. It exhibited multimodal antitumor mechanisms in TNBC models, including P21/P27-mediated G₀/G₁ arrest, DNA damage induction, and P53/Bax-dependent apoptosis with Bcl-2 downregulation. In MDA-MB-231 xenografts, compound <b>30</b> significantly inhibited tumor growth in a dose-dependent manner without observable toxicity. These findings highlight compound <b>30</b> as a promising therapeutic candidate for TNBC treatment through CSN5 inhibition, which simultaneously induces PD-L1 degradation and direct antitumor activity.