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Second-Generation AUTACs for Targeted Autophagic Degradation.

Daiki Takahashi1, Taiichi Ora2, Shigekazu Sasaki2

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Autophagy-targeted chimeras (AUTACs) are novel degraders. Replacing cysteine moieties in AUTACs significantly enhanced their degradation activity, improving their practical value for drug discovery.

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Area of Science:

  • Drug discovery and development
  • Molecular biology
  • Biochemistry

Background:

  • Targeted protein degradation is a key drug discovery strategy.
  • Autophagy, an intracellular degradation system, offers potential for targeting diverse substrates.
  • Previous work established autophagy-targeted chimeras (AUTACs) based on guanine modification and cysteine residues.

Purpose of the Study:

  • To investigate the role of the cysteine substructure in AUTACs.
  • To explore alternative moieties to cysteine for improved degrader activity.
  • To enhance the practical utility of autophagy-based targeted degradation.

Main Methods:

  • Structure-activity relationship (SAR) studies were conducted.
  • Cysteine residues in AUTACs were systematically replaced with other chemical groups.
  • Degradation activity of novel AUTAC derivatives was evaluated.

Main Results:

  • Significant improvements in degrader activity were observed upon replacing cysteine.
  • Several AUTAC derivatives demonstrated degradation activity in the sub-micromolar (sub-μM) range.
  • The importance of the cysteine substructure was elucidated, with non-cysteine derivatives showing enhanced efficacy.

Conclusions:

  • The cysteine substructure is not essential for AUTACs and can be replaced.
  • Optimizing AUTACs by modifying the cysteine moiety can lead to highly potent degradation agents.
  • These findings expand the scope and practical applicability of autophagy-targeted degradation in drug discovery.