There are about 514 different protein kinases operating in human cells, accounting for 2.5% of the entire human genome. For scientists who want to use targeted protein degradation (TPD) technology to destroy intracellular kinases, knowing which of these kinases can be degraded and which drug molecules can best degrade degradable kinases will accelerate their development of new therapies for cancer and other diseases.
In a study published in Cell, scientists from the Dana-Farber Cancer Institute identified about 200 degradable kinases and mapped the first biodegradable kinase map that will help researchers design molecules to target the degradation of these specific kinases which are expected to have a significant impact on cancer treatment.
Kinases play a key role in regulating cell protein activity, but in abnormal cases promote tumor cell proliferation, so kinases are also the main targets of cancer drugs. Previously, some targeted molecules have been designed to bind to these kinases (such as BTK and CDK4/6) to inhibit them, thereby slowing tumor cell growth or leading to tumor cell death. However, tumor cells can often overcome this effect and become resistant to kinase inhibitors, thus restoring growth.
In order to overcome the problem of drug resistance of kinase inhibitors and to have the opportunity to target kinases that have not yet developed corresponding inhibitors, scientists have developed a new technology, targeted protein degradation. The molecules developed based on this technology do not inhibit the disease-causing kinase by binding to the kinase, but directly destroy the disease-causing kinase.
In cells, a molecule called E3 (ubiquitin) ligase can be labeled as defective or damaged by attaching a small protein called ubiquitin to the target protein. After that, the intracellular protein shredder (that is, proteasome) degrades the labeled target protein. In 2004, three scientists from Israel and the United States won the Nobel Prize in chemistry for discovering this process of protein degradation mediated by ubiquitin. Targeted protein degradation is a new technology developed based on this mechanism, and the drugs developed based on this technology are called protein degradants.
Simply put, protein degradants that target kinases bind to a specific kinase at one end and to an E3 ligase at the other. After that, the E3 ligase marks the target kinase through ubiquitin, and finally the target kinase is degraded by the proteasome system.
Dr. Eric Fischer of the Dana-Farber Cancer Institute said targeting protein degradation has many advantages over standard targeted inhibition therapy. For example, protein degradants do not need to bind closely to the active sites of the target protein as protein inhibitors do. Protein degradants represented by PROTAC can specifically label it only by weakly binding to the target protein, so that the target protein can be degraded (traditional protein inhibitors need to have a strong binding to the active site of the target protein in order to play a role. However, it is estimated that 80% of proteins in human cells lack such sites.
However, although targeted protein degradation has shown great promise as a new anti-cancer therapy, there is no good answer as to how to build the most effective degradants and which kinases are most sensitive to these degradants.
“Targeted protein degradation is a new field. By creating a comprehensive data set, we hope to find out the rules behind the development of protein degradants, and then optimize the development of these new drugs.” Dr. Fischer said.
To create such a data set, Dr Fischer and his colleagues built a large library of degradants, then processed a group of cell lines expressing nearly 500 protein kinases and used mass spectrometry to see which kinases were degraded. In the end, they identified 172 degradable protein kinases, a significant increase compared to the 57 previously reported in the literature.
| AAK1 | CDK18 | FGFR1 | MAPK10 | PDK2 | SNRK |
| ABL1 | CDK2 | FGFR2 | MAPK11 | PDK3 | SRC |
| ABL2 | CDK4 | FYN | MAPK12 | PIK3CG | STK10 |
| ADCK3 | CDK4 | GAK | MAPK14 | PIM2 | STK17A |
| ADCK4 | CDK5 | GSG2 | MAPK6 | PKMYT1 | STK17B |
| AKT1 | CDK6 | GSK3A | MAPK7 | PKN3 | STK32C |
| AKT2 | CDK7 | GSK3B | MAPK8 | PLK1 | STK33 |
| AKT3 | CDK9 | HIPK1 | MAPK9 | PLK4 | STK35 |
| AURK4 | CHEK1 | IRAK1 | MAPKAPK2 | PRKAA1 | STK38 |
| AURKB | CLK1 | IRAK3 | MAPKAPK3 | PRKCI | STK4 |
| BCKDK | CSK | IRAK4 | MAPKAPK5 | PTK2 | STK40 |
| BLK | CSNK1A1 | ITK | MARK2 | PTK28 | TAOK2 |
| BMP2K | CSNK1D | LATS1 | MARK3 | PTK6 | TAOK3 |
| BMPRIA | CSNK1E | LCK | MARK4 | RIOK2 | TBCK |
| BTK | DAPK1 | LIMK1 | MAST3 | RIPK1 | TBK1 |
| BUB1 | DDR2 | LIMK2 | MELK | RIPK2 | TEC |
| BUB1B | EEF2K | LRRK2 | MINK1 | RPS6KA1 | TESK2 |
| C1T | EIF2AK2 | LYN | MKNK2 | RPS6KA3 | TGFR1 |
| CAMKK1 | EIF2AK4 | MAP2K5 | NEK1 | RPS6KA4 | TNK1 |
| CDC7 | EPHA1 | MAP3K1 | NEK2 | RPS6KA6 | TNK2 |
| CDK1 | EPHA2 | MAP3K11 | NEK3 | RPS6KB1 | TRIB3 |
| CDK10 | EPHA3 | MAP3K12 | NEK4 | RPS6KC1 | TRPM7 |
| CDK11A | EPHB2 | MAP3K21 | NEK9 | RRKAA2 | TTK |
| CDK11B | EPHB3 | MAP3K7 | NLK | SBK1 | TYK2 |
| CDK12 | EPHB4 | MAP4K1 | NUALK1 | SGK223 | UHMK1 |
| CDK13 | EPHB6 | MAP4K2 | PAK4 | SGK3 | ULK1 |
| CDK16 | ERN1 | MAP4K3 | PDIK1L | SIK2 | ULK3 |
| CDK17 | FER | MAP4K5 | PDK1 | SIK3 | VGFR1 |
| WEE1 | YES1 | ZAK |
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