A Novel CSN5 Inhibitor Drives Tumor-Intrinsic PD-L1 Degradation and Exerts Direct Antitumor Efficacy in
Yanjun Wang1, Hui Lei1,2, Wenyi Liu1,2
1Sichuan Provincial Engineering Research Center of Molecular Targeted Diagnostic and Therapeutic Drugs, College of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China.
Abstract:
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.
Insights
Novel azaindole derivatives targeting CSN5 show promise for triple-negative breast cancer (TNBC). Compound 30 effectively inhibits CSN5, degrades PD-L1, and exhibits potent antitumor activity in preclinical models.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- CSN5 is a key oncoprotein in triple-negative breast cancer (TNBC).
- CSN5 stabilizes PD-L1, promoting tumor progression.
- Targeting CSN5 is a potential therapeutic strategy for TNBC.
Purpose of the Study:
- To develop novel CSN5 inhibitors for TNBC treatment.
- To evaluate the antitumor activity and mechanisms of novel azaindole derivatives.
Main Methods:
- Synthesis and SAR analysis of 4-NH-substituted azaindole derivatives.
- In vitro assays to assess CSN5 inhibition, PD-L1 degradation, and cell cycle arrest.
- In vivo studies using MDA-MB-231 xenograft models.
Main Results:
- Compound 30 identified as a potent CSN5 inhibitor (IC50 = 0.58 μM).
- Compound 30 induced PD-L1 degradation and triggered apoptosis via P53/Bax pathway.
- Significant tumor growth inhibition in TNBC xenografts without observable toxicity.
Conclusions:
- Compound 30 demonstrates multimodal antitumor activity through CSN5 inhibition.
- This novel azaindole derivative is a promising therapeutic candidate for TNBC.
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