Indole derivatives for targeting autophagy

NZ834882AUndetermined Publication Date: 2025-07-31AUTOMERA PTE LTD
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Patent Information

Application Number
NZ834882
Authority / Receiving Office
NZ · NZ
Patent Type
Applications
Current Assignee / Owner
Priority Date
2024-01-24
Filing Date
2025-01-23
Publication Date
2025-07-31

AI Technical Summary

Technical Problem

Current therapies for modulating autophagy, particularly targeting p62, are limited in their ability to induce selective degradation of pathogenic proteins, and existing technologies like PROTACs face challenges in forming substrate-PROTAC-E3 ligase complexes, restricting their application to a limited set of targets and E3 ligases.

Method used

Development of novel heterobifunctional compounds that engage the autophagy adaptor protein p62/SQSTM1, triggering its activation and subsequent assembly of autophagosomes, comprising a targeting ligand and a p62 activating moiety connected by a flexible linker, to enhance the sequestration of targeted proteins within nascent autophagosomes.

Benefits of technology

This approach allows for precise orchestration of p62 oligomerization and spatial localization, harnessing the cell's autophagic machinery to therapeutically degrade specific targets, including proteins, protein aggregates, and pathogens, offering a broad-spectrum therapeutic modality for diseases characterized by aberrant protein accumulation or defective protein clearance.

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Abstract

Provided herein are compounds of formula (I), (II), and (III), or pharmaceutically acceptable salts, stereoisomers, or deuterated forms thereof, wherein X1, X2,Y1, Y2, Y3, R1, R2, a, b, L0, L1, L2, and A are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I), (II), or (III), or pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof, and methods of using a compound of formula (I), (II), or (III), or pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof, e.g., in the treatment of a disease or disorder by modulating autophagic degradation and / or p62 activity.
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