What are PROTAC Linkers?

What are PROTAC Linkers?

Published by BroadPharm on December 12, 2022

PROTACs, proteolysis targeting chimeras, are heterobifunctional small molecules composed of three distinct components: a warhead that binds to a target protein or protein of interest (POI), an anchor that binds to an E3 ubiquitin ligase, and a linker that conjugates the two ligands together (Figure 1). PROTACs take advantage of the ubiquitin-proteasome system (UPS), which is the waste disposal system of cells. This mechanism of PROTACs functions effectively at lower dosages, with reduced toxicity, and with prolonged pharmacodynamics when compared with more traditional inhibitors.

Figure 1: General structure of a PROTAC. The specific POI targeting "warhead" (blue) is connected to the E3 ligase targeting "anchor" (yellow) via a PROTAC linker.

It is becoming apparent that the linker plays a critical role in the physicochemical properties and bioactivity of the molecule. The length of the linker determines to what degree the two ligands interact and thus the maximal activity of the PROTAC molecule. Cyrus’s group determined that the optimal linker length for estrogen receptor (ER)-α targeting PROTACs is 16 atoms long; however, they noted that the optimal distance between the two ligands of any given PROTAC will need to be determined on a case-by-case basis.

There are a few common chemical motifs that occur often in PROTAC linker design. These motifs were recently highlighted by Maple’s group in a database they compiled of over 400 protein degrader structures. The most common motifs incorporated into PROTAC linker structures are PEG, Alkyl, and other glycol chains of varying lengths (Table 1).

Table 1: The three most commonly occurring PROTAC linker motifs in the Maple database.


Linker Motif

% in Published Research





Other Glycol



(S,R. S)-AHPC-PEG linker (Figure 2) is a PROTAC linker molecule that incorporates a von Hippel-Lindau (VHL) E3 ligase ligand with a PEG linker. The VHL recruiting ligand is one of the most widely used E3 ligands in PROTAC technology. The PEG spacer increases reagent's solubility in aqueous media. This molecule allows for parallel synthesis to be used to generate PROTAC libraries that feature variation in crosslinker length, composition, and E3 ligase ligands due to the ability to select from many different types of functional groups on the PEG linker.

Figure 2: Structure of (S,R.S)-AHPC-PEG linker can attach different functional groups for bonding with POI ligands, such as carboxyl, amine, azide, alkyne, Tos, TCO, DBCO, etc.

The Pomalidomide based Cereblon (CRBN) ligand is another widely used E3 ligand. For example Pomalidomide-PEG5-Azide (Figure 3) is a CRBN ligand with a 5-unit PEG linker and a terminal azide. The azide group on this PROTAC technology enables click chemistry with alkyne, DBCO, and BCN molecules. This has been corroborated by a high number of different synthetic approaches and provides a basis for their importance in the future of PROTAC design.

Figure 3: Structure of Pomalidomide-PEG5-Azide.

As a worldwide leading supplier of PROTAC Linkers and biochemical reagents, BroadPharm offers a wide variety of linkers to empower our clients' advanced research and formulations. Please visit our website at www.broadpharm.com. You can also call 1-(858)-677-6760 or email sales@broadpharm.com for any assistance.