PROTAC

There are several challenges towards the development and clinical use of small molecule inhibitors, which are currently the main type of targeted therapies towards intracellular proteins. PROteolysis-TArgeting Chimeras(PROTACs) exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins. Recently, small-molecule PROTACs with high potency have been frequently reported. The outstanding advantages over traditional small-molecule drugs and the promising preclinical data suggest that small-molecule PROTAC technology has the potential to greatly promote the development of targeted therapy drugs.

Hetero bifunctional protein degraders contain a target-binding warhead on one end and an E3 ubiquitin ligase-targeting ligand on the other, connected by a linker in the middle. When the degrader is applied, it recruits the target to the E3 ligase. Once in proximity of the E3 ligase, the target is poly ubiquitinated, flagging it for degradation via the proteasome.

PROTAC Design

From the structural characteristics of PROTAC, the design considerations are mainly as follows:

Selection of POI ligands: POI ligands are typically selected from either listed or literature-reported inhibitors with certain activity. PROTAC may be created in order to have an intellectual property on a drug, for which a structural derivatization is often done before it’s used as a ligand for POI.
Selection of E3 ligases and their ligands: The most common E3 ligases reported in literature for use with PROTAC are active CRBN, VHL, cIAP, and MDM2 among which the more effective and commonly used ones are CRBN and VHL. Among them CRBN has a variety of ligands; lenalidomide, pomalidomide analogues, meanwhile the VHL has much less diverse set such as ribavirin analogues or sorafenib analogues only.

Selection of Linker: Generally, alkyl chains (4-15 carbon or hetero atoms), PEG chains (1-10) or extended glycol Chains are the most often used as linkers in PROTAC. In accordance to the target site different linker length will result in different effects on degradation activity.

Inhibition vs Degradation

Traditional Drugs	PROTAC Degraders
Active Site required	Active Site not required
Transient and Less Durable	Sustained Degradation
Higher Drug exposures required	Lower doses for Potent Degradation
Strong binding required	Weak binding is sufficient
Target of 1 function	Target of all functions
Isoform Non-Specific	Isoform Specific
Inhibition of a Subunit	Degradation of a Complex

PROTAC

PROTAC

PROTAC Design

Inhibition vs Degradation

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