Methods and compositions for UBA5 inhibition

WO2026090386A3 Publication Date: 2026-06-04THE ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIV OF ARIZONA
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Patent Information

Application Number
PCT/US2025/052219
Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
Priority Date
2024-10-24
Filing Date
2025-10-23
Publication Date
2026-06-04

AI Technical Summary

Technical Problem

Current technologies lack effective high-throughput screening strategies for selective UBA5 inhibitors, which are crucial for modulating the UFMylation pathway implicated in diseases such as Alzheimer's disease and cancer, and existing inhibitors often lack specificity or have weak inhibitory effects.

Method used

Development of a robust high-throughput screening assay using the AMP-Glo™ kit to identify and characterize novel UBA5 inhibitors with low micromolar IC₅₀ values, spanning diverse chemical scaffolds, demonstrating selectivity for UBA5 over other E1 enzymes and inhibiting endogenous UFMylation in HEK293T cells.

Benefits of technology

The identified inhibitors provide precise UBA5 inhibition, offering therapeutic potential for diseases associated with dysregulated UFMylation, including Alzheimer's disease and cancer, while avoiding adverse effects due to UBA5's critical role in cellular stress responses.

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Abstract

UBAS is a critical El-activating enzyme in the UFMylation pathway, a post-translational modification process implicated in neurodegenerative diseases and cancers. Here, a high-throughput screening (HTS) assay was developed to identify inhibitors of UBAS from various compound libraries. Eighteen novel UBAS inhibitors were identified, belonging to several distinct chemical scaffolds with low micromolar IC50 values. These inhibitors demonstrated selectivity for UBAS over other El enzymes, including UBA1, and showed efficacy in inhibiting endogenous UFMylation in HEK293T cells. The identified inhibitors not only provided valuable tools for studying UFMylation but also represented potential therapeutic candidates for diseases associated with dysregulated UFMylation, such as Alzheimer's disease and cancer.
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