Dual-Action-Only PROTACs

  • J Am Chem Soc. 2025 Mar 19;147(11):9074-9078. doi: 10.1021/jacs.5c00131.
Ranit Dutta  1  2 ,  Anirudh Devarajan  1  2 ,  Amelia Talluri  1 ,  Ritam Das  1  2 ,  S Thayumanavan  1  2  3
Affiliations
  • 1. Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States.
  • 2. Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States.
  • 3. Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States.
PMID: 40063962 DOI: 10.1021/jacs.5c00131
Abstract

Proteolysis targeting chimera (PROTAC)-based degraders are highly potent pseudocatalytic drugs, but on-target off-site homing could yield undesirable consequences. We report here a generalizable AND-logic gated PROTAC, where the concurrent presence of two different disease-relevant endogenous stimuli liberates an active protein degrader. We design Dual-Action-Only PROTAC (DAO-PROTAC) molecules that are dormant and can only be activated in the presence of both hypoxia and cathepsin-L to degrade the protein of interest (POI). We also show that the dormancy of DAO-PROTACs translates to considerable mitigation of cytotoxicity, demonstrating the potential advantages over the corresponding free PROTAC and single-stimulus triggerable pro-PROTACs.

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