PROteolysis Targeting Chimera (PROTAC) drugs

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

Advantages:

Taking aim at the "Undruggable"
Multiple delivery methods
The ability to cross blood-brain barrier
Possibility of tissue-specific targeting
Benefits of tiny molecules

Why PROTAC？

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).

Reference

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

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