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​PROteolysis Targeting Chimera (PROTAC) drugs

Heterobifunctional molecules that highjack ubiquitin ligase and targets cellular proteins for degradation. 


  • Taking aim at the "Undruggable"

  • Multiple delivery methods

  • The ability to cross blood-brain barrier 

  • Possibility of tissue-specific targeting 

  • Benefits of tiny molecules


What are the advantages of PROTAC over other molecular glue degraders?

PROTAC Discovery Workflow


What are the challenges?

  • Membrane permeation mechanism 

  • Temary crystal structures difficult to capture or identify

  • ADME & toxicity studies

What are the disadvantages?

  • Size-induced difficulties in clinic 

  • Lengthy discovery phase 

  • Off-target effect 

  • Hook effect

PROTAC drug development:

  • Degradation efficacy: Time and degradation percentage.

  • Hook effect: Negatively impacts target degradation with excessive concentration of PROTAC.

  • Cooperativity: Favorable interactions between target protein and E3 ligase enable positive cooperativity

    occurs when repulsive interactions inhibit the ternary complex formation.

PROTAC-mediated ternary complex formation and hook effect. The hook effect is a function of PROTAC concentration (black line). A possible strategy to reduce the hook effect is increasing cooperative-binding PPIs to stabilize ternary complexes (red line).


  1. Cecchini C, Pannilunghi S, Tardy S, Scapozza L. From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation. Front Chem. 2021;9:672267. Published 2021 Apr 20. doi:10.3389/fchem.2021.672267

For one-stop PROTAC service please click here.