Cell: Article reveals more than 100 potential PROTAC targets (with detailed list)

In human cells, there are about 514 different protein kinases that make up 2.5 percent of the entire human genome.
For scientists who want to use Targeted Pprotein Degradation (TPD) technology to destroy in-cell kinases, understanding which of these kinases can be degraded and which drug molecules can best degrade biodegradable kinases will accelerate their development of new therapies for the treatment of cancer and other diseases.
a recent study published in the journal Cell, scientists from the Dana-Farber Cancer Institute identified about 200 biodegradable kinases and mapped them for the first time.
this map will help researchers design molecules that can target the degradation of these specific kinases, which is expected to have a significant impact on cancer treatment.
kinases play a key role in regulating cell protein activity, kinases can promote tumor cell proliferation in abnormal situations, making kinases a major target for cancer drugs.
previously, targeted molecules were designed to bind to these kinases (e.g. BTK, CDK4/6) to inhibit their function, thereby slowing tumor cell growth or causing tumor cell death.
, however, tumor cells are often able to overcome this effect by developing resistance to kinase inhibitors and thus restoring growth.
in order to overcome the problem of kinase inhibitor resistance and have the opportunity to target kinases that have not yet developed the corresponding inhibitors, scientists have developed a new technique, target protein degradation (TPD).
developed based on this technique does not act as inhibitors by binding to kinases, but directly destroys disease-ing kinases.
in cells, a molecule called E3 (Ubilin) connective enzyme can mark a small protein called ubibin on the target protein as defective or damaged.
, the protein shredder (i.e., protease) in the cell degrades the labeled target protein.
2004, three scientists from Israel and the United States won the Nobel Prize in Chemistry for discovering "the protein degradation process mediated by ubibin."
target protein degradation is a new technology developed based on this mechanism, based on the drug called protein degradation agent.
simple terms, protein degradation agents that target kinases bind to a specific kinase at one end and an E3 connective enzyme at one end.
, the E3 connective enzyme marks the target kinase by ubibin, and finally the target kinase is degraded by the protease system.
Eric Fischer, of the Dana-Farber Cancer Institute, says there are many advantages to targeted protein degradation over standard targeted inhibitors.
For example, protein degradation agents do not need to rely on close binding to target protein activity points like protein inhibitors, and protein degradation agents represented by PROTACs only need to bind weakly with target proteins to specifically "mark" it, thereby degrading the target protein (traditional protein inhibitors require strong binding to target protein activity points to function, however, it is estimated that 80% of proteins in human cells lack such a point).
However, while targeted protein degradation has shown great prospects as a new type of anticancer therapy, there is no good answer as to how to build the most effective degradation agents and which kinases are most sensitive to them.
" targeted protein degradation is a new area.
we hope to optimize the development of these new drugs by creating a comprehensive data set that identifies some of the patterns behind protein degradation drug development.
," Dr. Fischer said.
To create such a data set, Dr Fischer and his colleagues built a large library of degradation agents, then processed a group of cell families that expressed nearly 500 protein kinases and used mass spectrometry to see which kinases were degraded.
, they identified 172 biodegradable protein kinases, a significant increase from the 57 previously reported in the literature.
Table 1 More than 170 biodegradable protein kinases Source: Cell Table 2 57 biodegradable kinase Data sources previously reported: Cell In addition, studies have shown that 136 of the 172 biodegradable kinases can be Among the two independent compound degradation, CDK4, AURKA, FER, WEE1, BLK, LIMK2, CDK6, GAK and LIMK1 are 9 kinases that can be degraded by at least 40 independent compounds, indicating that they are easily induced to degrade.
Images The most induced-degraded protein kinase TOP20 (source: Cell) Fischer said: "For researchers who want to develop a specific kinase protein degradation agent, they first need to know whether the kinase can be degraded, and secondly, what type of degradation agent may be most effective.
using our database, researchers can determine whether the kinases they are interested in are biodegradable and which molecules can perform this degradation task.
" in addition to providing a significant database, the new study also made some discoveries that go against the instincts of many scientists.
, for example, some scientists have speculated that the most effective degradation agents may be those with the highest affinity with kinases, the molecules that bind most closely, but this is not the case.
data set, built by Dr Fischer and his partners, shows that the highest affinity does not determine that the degradation agent is most effective, and other factors are important.
"We believe this work will not only facilitate the discovery and development of new kinase degradation agents, but will also help us deepen our understanding of the new technology of target protein degradation."
," concluded Dr Fischer.
: 1 s new map provides scientists with head start on how how to destroy cancer-related enzymes why just block them (Source: Dana-Farber Cancer Institute) 2 s Katherine A. Donovan et al. Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell(2020).