Over the past decade, major changes have taken place in the field of drug targets. Although the traditional target is still the main direction, the R&D trend is gradually shifting from traditional drug targets to the more challenging “undruggable drug” target. These targets usually include proteins that have no enzyme function, which account for about 80% of human proteins. The hot protein proteolysis-targeting chimera (PROTAC) technology shows great potential in overcoming drug resistance and targeting previously “undruggable” targets.
Ubiquitin-proteasome system (UPS) is the main pathway of intracellular protein degradation, which participates in the degradation of more than 80% of intracellular proteins. PROTAC technology uses UPS to induce targeted protein degradation, which has many advantages, such as targeting “undruggable” targets, targeting mutated overexpressed proteins, and excellent pharmacokinetic effects. Taking advantage of the cell’s own UPS, PROTAC induces the target protein to form a ternary complex with E3 ubiquitin ligase by using a bifunctional small molecule that can bind the target protein to E3 ubiquitin ligase at the same time, and makes the target protein be recognized by E3 ubiquitin ligase and then be ubiquitinated, and finally recognized and degraded by the proteasome in the cell.
The action mechanism of PROTAC is different from that of traditional drugs. Most small molecular inhibitors and antibody drugs exert their effects through occupancy-driven pharmacology, that is, they inhibit the function of proteins or enzymes by combining with the active sites of target proteins and competing with endogenous substrates. There are certain requirements on the affinity between the drug and the target protein, the half-life of the drug, and so on. Small molecule interference RNA has a short half-life and is easy to degrade. Although GalNAc coupled RNA technology has successfully achieved liver targeting and improved the escape rate of RNA, drug delivery still remains a problem. PROTAC is different from the above-mentioned drugs. First of all, it does not have to bind to the active site of the target protein in order to play a role. Only moderate binding ability to the inactive site of the target protein enables the degradation of the target protein. Secondly, in the whole process, PROTAC acts as a “matchmaker”, bridging the E3 ligase and the target protein, which is then released when the target protein and E3 ligase are close to each other after ubiquitination, and continues to match the next pair. In this way, the PROTAC degradation of proteins has catalytic properties, and low doses can play a role.
Research updates of PROTAC technology
- PROTAC-DB data
After more than 10 years of accumulation, the scientific and industrial circles have developed thousands of PROTAC molecules. In an article published in Nucleic Acids Research, a research team from Zhejiang University proposed an open database PROTAC-DB based on Web. As of April 17, 2021, the library contains more than 200 targets with a total of 2,258 PROTACs, 275 Warhead, 68 E3 ligands, and 1,099 linkers.
- Top 10 PROTACs
At the PROTAC level, the top 10 PROTAC targets are ER, BRD4, AR, CDK4, CDK6, BTK, ALK, BCR-ABL, MEK1, and Bcl-xL.
Among them, the largest number of targets is ER (breast cancer), the second is BRD4 (blood cancer, breast cancer, colon cancer, etc.), the third is AR (breast cancer, prostate cancer, etc.).
- Top 10 Warheads
At the Warhead level, the top 10 targets are AR, ER, AURK4, BRD4, BTK, CDK4, CDK9, FAK, IRAK4, and Weel.
Among them, the largest number of targets is AR (27), the second is ER (26), and the third is AURKA (lymphoma) with 23.
- Top 10 Linkers
At the Linker level, the top 10 targets are CDK4, CDK6, BRD4, AR, BTK, ER, MEK1, BCR-ABL, ALK, and CDK2.
The largest number of targets is CDK4 (breast cancer), the second is CDK6 (breast cancer), and the third is BRD4.
- Top 10 E3 Ligands
At the E3 ligand level, the top 10 targets are AR, ER, BRD4, CDK4, CDK6, BRD2, BRD3, BTK, BRD9, EGFR L858R/T790M, and IRAK4.
The largest number of targets among them is AR (28), the second ER (26), and the third BRD4 (23).
- According to incomplete statistics, there are more than 60 R&D pipelines based on PROTAC technology.
There are estimated more than 60 research and development pipelines based on PROTAC technology worldwide, including 2 clinical Phase II drugs, Arvinas Inc’s ARV-471 and ARV-110, for the treatment of breast cancer and prostate cancer respectively, and 6 clinical Phase I drugs, including NX-2127 from Kymera Therapeutics and KT-474 jointly developed by Kymera Therapeutics and Sanofi. There are more than 50 in preclinical and R&D stages. According to the PROTAC review published in Nature Reviews Drug Discovery in March 2021, it is speculated that at least 15 PROTAC drugs will enter the clinical stage by the end of 2021.