Molecular glue degrader mediated by e3 ubiquitin ligase fbxo22 and applications thereof

By designing an E3 ubiquitin ligase FBXO22-mediated molecular glue degrader and utilizing alkylamine substituents to bind BRD4, the permeability and selectivity issues of PROTAC technology were solved, achieving efficient degradation and anti-fibrotic effects on BRD4 protein.

CN121717822BActive Publication Date: 2026-06-05SHENZHEN UNIV
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
SHENZHEN UNIV
Filing Date
2026-02-25
Publication Date
2026-06-05

AI Technical Summary

Technical Problem

Existing targeted protein degradation technologies such as PROTAC suffer from problems such as poor cell membrane permeability, low oral bioavailability, complex molecular design, poor pharmacokinetic properties, and off-target toxicity. Furthermore, the different tissue expression profiles of E3 ubiquitin ligases make selective degradation difficult.

Method used

We designed an E3 ubiquitin ligase FBXO22-mediated molecular glue degrader, which binds to the target protein BRD4 via an alkylamine substituent. We then used FBXO22 to mediate the targeted degradation of bromine domain proteins and verified its degradation activity using high-content screening and Western blotting techniques.

Benefits of technology

This study achieved efficient degradation of BRD4 and its family proteins, blocked related downstream pathway signals, and exhibited cancer cell death-inducing and anti-fibrotic activities, providing a new direction for drug research in the treatment of bromodomain protein-related cancers and fibrotic diseases.

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Abstract

The application discloses an E3 ubiquitin ligase FBXO22-mediated molecular glue degrader and application thereof, and relates to the technical field of medicinal chemistry. Based on the principle of targeted protein degradation, a series of E3 ubiquitin ligase FBXO22-mediated molecular glue degraders are designed and synthesized. The structure of the molecular glue degrader is shown in formula I or formula II: wherein R 1 and R 2 at least one contains alkylamine substitution. The application screens the activity of the compound by high-content screening technology and Western blotting technology, confirms that the molecular glue degrader can induce the degradation of bromodomain-containing protein 4 and other proteins in its family by E3 ubiquitin ligase FBXO22, thereby can hinder the relevant downstream pathway signals, has the activity of inducing cancer cell death and anti-fibrosis, and is expected to provide a new drug research direction for the treatment of bromodomain protein-related cancer and fibrosis diseases.
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