Preparation method of inhibitor targeting MAX-PD-L1 promoter specific binding motif and double-target inhibitor

By developing an inhibitor preparation method that specifically binds to the MAX-PD-L1 promoter motif, the problem of drug resistance caused by existing anti-PD-L1 inhibitors failing to block PD-L1 expression in tumor cells has been solved. This method achieves highly specific and high-affinity inhibition of tumor immune escape, thereby improving the efficacy of immunotherapy for lung adenocarcinoma.

CN121915040APending Publication Date: 2026-04-24GENERAL HOSPITAL OF SOUTHERN THEATRE COMMAND OF PLA
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Patent Information

Application Number
CN202511978769.5
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2025-12-25
Publication Date
2026-04-24

AI Technical Summary

Technical Problem

Existing anti-PD-L1 inhibitors cannot effectively block tumor cells from reactivating PD-L1 expression through upstream regulatory pathways, leading to drug resistance. Furthermore, existing inhibitors do not target the PD-L1 transcriptional activation process, failing to address the issue of multi-mechanism synergistic escape.

Method used

The method for preparing inhibitors that specifically target the MAX-PD-L1 promoter binding motif includes enriching chromatin DNA fragments from target cancer cells, screening for specific binding motifs, designing high-affinity DNA aptamers and small molecule compounds, optimizing their affinity and cell permeability, screening for highly active inhibitors using EMSA and SPR experiments, and preparing dual-target inhibitors that simultaneously target the MAX and JAK1 kinase domains.

Benefits of technology

It significantly inhibits tumor immune escape, enhances the killing rate of T cells against tumor cells, improves the response rate of immunotherapy for lung adenocarcinoma, and has high specificity and high affinity, while reducing off-target effects.

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Abstract

The invention relates to the technical field of biological medicines, in particular to a preparation method of an inhibitor targeting a MAX-PD-L1 promoter specific binding motif and a double-target inhibitor, through ChIP-seq and site-directed mutagenesis experiments, a core binding motif of MAX and a PD-L1 promoter, such as 5 '-CAC [GA] TG-3', is defined, it is ensured that the inhibitor only targets a key site of MAX-PD-L1 interaction, and the activity of the MAX-PD-L1 promoter specific binding motif is improved. The off-target effect is avoided, and a high-specificity target spot is provided for subsequent inhibitor design. The cell permeability of the DNA aptamer screened based on the specific binding motif is improved after cholesterol modification, and the affinity of the DNA aptamer is obviously higher than that of a traditional antibody. A small molecule compound virtually screened through a molecular docking model is optimized through hydrogen bond and hydrophobic interaction, and then the binding affinity with MAX is improved. After treatment with the inhibitor, the combination inhibition rate of MAX and the PD-L1 promoter is high, the transcriptional activity of PD-L1 is obviously reduced, the killing rate of T cells to tumor cells is also improved, and immune escape is effectively blocked.
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