Blockbuster: 1336 PROTAC targets revealed in Nature

PROTAC, proteolysis targeting chimera, or proteolytic targeted chimera, is a new type of drug different from antibodies and traditional small molecule inhibitors.

PROTAC consists of target protein binder, linker, and E3 ubiquitin ligase binder. In other words, one end of PROTAC binds to the target protein and the other binds to E3 ubiquitin ligase that can mark a small protein called ubiquitin as defective or damaged once attached to it. After that, the cell’s protein shredder—proteasome recognizes and degrades the labeled target protein. Based on this mechanism, PROTAC molecules are also called protein degradants.

The field has grown by leaps and bounds since the first small molecule PROTAC was reported by a team of professors at Yale University in 2008. After more than 10 years of accumulation, the scientific and industrial communities have developed thousands of PROTAC molecules. By now, PROTAC molecules targeting AR, ER, BTK, IKZF1/3, BRD9, Bcl-xl, IRAK4 and other proteins have entered the clinical development stage, and the fastest project is in phase I/II, involving adaptive syndrome such as prostate cancer, breast cancer, non-Hodgkin’s lymphoma, multiple myeloma, B-cell lymphoma, atopic dermatitis, androgenic alopecia, and acne.

One of the major advantages of PROTAC technology is its ability to shift the “non-druggable” target to “drug-free”. Traditional small molecular inhibitors need to bind firmly to target proteins (in most cases the active sites). It is estimated that 80% of proteins in human cells lack such sites, which still have the chance become potential drug targets as PROTAC only needs to bind weakly to the target protein to specifically “label” it.

In a Perspective published in the journal Nature Reviews Drug Discovery on July 20th, a team of scientists from the United Kingdom proposed a systematic method to evaluate the PROTACtability of protein targets. Using this method, they identified 1,067 PROTAC targets that have not been reported in the literature, providing new opportunities for PROTAC-based drug development.

Specifically, in order to facilitate extensive genome-wide analysis, the researchers divided the targets into four groups according to different progress statuses, which are clinical precedence, literature precedence, discovery opportunity, and incomplete evidence.

* Targets with clinical precedence

The targets of this group have entered the stage of clinical development, and the targets with literature precedence are targets that have been reported in the literature.

* Targets with discovery opportunity

PROTAC targets with development opportunities should meet the following conditions:

1. It is in at least one of the ubiquitylation buckets.
2. Havevalidated half-life data.
3. A small-molecule binder is reported in ChEMBL.
4. The PROTAC location score has high or medium confidence for a good or a grey location (location score of 1, 2, 3, or 4).

* Target with incomplete evidence

Using this rule of classification, scientists evaluated 19,498 proteins and identified 1,067 PROTAC targets with development potentials, 265 targets reported in the literature, and 4 entering the clinical development stage, obtaining a total of 1,336 PROTAC (PROTACtable) targets.

The researchers pointed out that this analysis provides the first assessment of a potential PROTACtable genome, and they expected significant evolution of the PROTACtable genome or degradable genome shortly.