Our beginner’s guide to PROTACs and targeted protein degradation is now out in The Biochemist

  • Figure 1. The Journey of a PROTAC. Cartoon depiction of the journey of a PROTAC molecule, starting with entry into the cell and resulting in degradation of a protein target. Once complete, the PROTAC is free to repeat the cycle. *The binary interaction step can occur with either E3 ligase or protein target.
  • Figure 2. Example of a ternary complex. X-ray crystal structure of PROTAC 1 (green) bound in a ternary complex with the bromodomain of its protein target SMARCA2 (pale orange) and the E3 ligase VHL (teal).
  • Figure 3. Examples of PROTAC chemical structures. Chemical structures of three BRD4 degraders: (left to right) CRBN-based dBET6, VHL-based MZ1 and IAP-based SNIPER(BRD)1.

Read the full article open-access here.

Authors: Alessio Ciulli* and Nicole Trainor

Title: A beginner’s guide to PROTACs and targeted protein degradation


  • PROTACs are molecules which cause protein degradation.
  • Protein degradation is akin to gene knockout: it can provide insight into the cellular functions of proteins.
  • Simultaneous binding of a target protein and an E3 ligase by a PROTAC within a key ternary complex facilitates ubiquitylation of the target protein.
  • The ubiquitylated target protein is degraded by the proteasome.
  • This mechanism of action can be catalytic.
  • The selectivity of PROTAC-mediated degradation can be superior to inhibition.
  • PROTACs may recruit targets via any binding site – functional and sustained inhibition is not required.
  • Targeted protein degradation offers new opportunities to tackle previously undruggable proteins.



Those with a keen interest in targeting proteins, from chemical biologists to drug hunters alike, cannot help but take notice that a new type of molecule is making waves across this research space. Proteolysis Targeting Chimeras (or PROTACs) are protein degraders, which utilize the cell’s own waste disposal machinery to eliminate instead of inhibit a target protein. The key to PROTACs is their bifunctionality: they simultaneously bind a target protein and an E3 ligase protein, which then ubiquitylates the target, marking it for proteasomal degradation. This concept originated in the late 1990s and the first PROTAC was reported in 2001 by the laboratories of Craig Crews and Raymond Deshaies. However, interest in PROTACs did not pick up until 2015 when improved molecules were developed by the laboratories of Jay Bradner, Alessio Ciulli and Craig Crews. Ever since, PROTACs and the wider field of targeted protein degradation have expanded exponentially, with many groups around the world developing degraders as chemical tools to study proteins and as drug candidates for the treatment of diseases.