E3 ubiquitin ligase FBXO22 mediated molecular glue degradation agent and application thereof

By designing a molecular glue degrader mediated by the E3 ubiquitin ligase FBXO22, the cell permeability and selectivity problems of PROTAC technology were solved, achieving efficient degradation and anti-fibrotic activity of BRD4 protein, providing a new direction for drug research in the treatment of diseases related to bromine domain proteins.

CN121717822AActive Publication Date: 2026-03-24SHENZHEN UNIV
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2026-02-25
Publication Date
2026-03-24

AI Technical Summary

Technical Problem

Existing targeted protein degradation technologies such as PROTAC suffer from problems such as poor cell membrane permeability, complex dual pharmacophore design, large molecular structure leading to rapid in vivo clearance and off-target toxicity, and different tissue expression profiles of E3 ubiquitin ligases make selective degradation difficult.

Method used

We designed a molecular glue degrader mediated by the E3 ubiquitin ligase FBXO22, which binds to the target protein BRD4 via alkylamine substituents. We then used FBXO22 to mediate the targeted degradation of the bromine domain protein. The activity of the compound was confirmed by combining high content screening technology and protein immunoblotting technology, thus developing a molecular glue degrader with BRD4 degradation activity.

Benefits of technology

It achieves efficient degradation of BRD4 and its family proteins, blocks related downstream pathway signals, and has the activity of inducing cancer cell death and anti-fibrosis, providing a new therapeutic direction for bromodomain protein-related cancers and fibrotic diseases.

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Abstract

The invention discloses an E3 ubiquitin ligase FBXO22 mediated molecular glue degradation agent and application thereof, and relates to the technical field of medicinal chemistry. The invention designs and synthesizes a series of E3 ubiquitin ligase FBXO22 mediated molecular glue degradation agents on the basis of a targeted protein degradation principle. The structure of the molecular glue degradation agent is shown as a formula I or a formula II, and at least one of R1 and R2 contains alkylamine substitution. The activity of a compound is screened through a high content screening technology and a protein immunoblotting technology, and it is confirmed that the molecular glue degradation agent can induce degradation of bromodomain protein 4 and other proteins in the family of the bromodomain protein 4 by using E3 ubiquitin ligase FBXO22, so that related downstream channel signals can be hindered; the compound has cancer cell death induction and anti-fibrosis activity, and is expected to provide a new drug research direction for treatment of bromodomain protein related cancers and fibrosis diseases.
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