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 4-NH-substituted azaindole derivatives as potent CSN5 inhibitors. Among them, through systematic structural modifications and SAR analysis at key positions, we identified 30 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 30 significantly inhibited tumor growth in a dose-dependent manner without observable toxicity. These findings highlight compound 30 as a promising therapeutic candidate for TNBC treatment through CSN5 inhibition, which simultaneously induces PD-L1 degradation and direct antitumor activity.