In the past 20 years, Protein Degrader has ushered in a period of rapid development, especially since the successful degradation of BET protein by dBET1 Protein Degrader with pomalidomide as the ligand of an E3 ligase in 2015. The research papers related to Protein Degrader have been growing explosively in the last two years. According to Rao’s team, Protein Degrader degraded more than 40 protein targets in 2019, and more than 130 protein targets were available for degradation by Protein Degrader by the end of 2021. It means that in 2020 and 2021, there were an additional 90 or so new protein targets that Protein Degrader might be able to degrade. These targets cover a wide range of diseases, primarily in the area of cancer, including immune disorders, viral infections, neurodegenerative diseases, and many others.
According to incomplete statistics, different degradation agents based on Protein Degrader technology can degrade about 54 kinds of kinases, accounting for 45% of the total targets. Researchers prefer kinases as the target for protein degradation, mainly because most kinases have known and effective inhibitors or ligands that can be easily modified to connect to linkers and maintain sufficient binding affinity. In addition, kinases have deep binding pockets, which can promote the binding of Protein Degrader, thus inducing the interaction between kinases and E3 ligases, and then ubiquitin and eventually degrading kinases. Moreover, although kinase proteins are highly homologous, Protein Degrader can selectively degrade different subtypes of kinases.
So far, 518 kinases have been found, which are involved in physiological regulatory processes such as cell survival, proliferation, differentiation, apoptosis, and metabolism. According to their structure and function, these kinases can be divided into nine categories, tyrosine kinases (RTKs), TKLs, STEs, CAMKs, AGCs, CMGCs, and atypical protein kinases (Atypical), CK1 and others.
Because it was developed based on POI inhibitors, Protein Degrader still has a certain off-target effect. And due to its large molecular weight, poor cell membrane permeability, and poor pharmacokinetic performance, Protein Degrader significantly reduced its biological and therapeutic effects. Although some Protein Degraders can effectively induce the degradation of target proteins, their biological effects are weak and ineffective on diseases. Most proteins do not have corresponding small molecular conjugates to design Protein Degraders, such as transcription factors that play a critical role in the occurrence and development of disease. Due to the few inhibitors of transcription factors, there is no binder available when designing Protein Degraders targeting transcription factors, which prominently limits the application of Protein Degrader technology. In recent years, Protein Degrader technologies have emerged to solve the above problems, such as antibody-Protein Degrader, aptamer-Protein Degrader conjugates, dual-target Protein DegraderS, folate-caged Protein Degraders, and TF-Protein Degraders.
- Antibody-Protein Degrader
Antibody-Protein Degrader is a new strategy to explore the assembly of new antibody-Protein Degrader conjugates by binding with antibodies. This technique can realize the specific degradation of proteins in different cells and tissues to optimize the treatment window, maximize the treatment window, reduce the side effects of broad-spectrum Protein Degrader, and increase its potential as a drug or chemical tool.
- Aptamer-Protein Degrader Conjugates
The nucleic acid aptamer is a single-stranded nucleic acid with a complex three-dimensional structure, mainly including stem, ring, hairpin, and G4 polymer. They bind to the target protein through hydrogen bonding, van der Waals force, base superposition force, and electrostatic effect, have high specificity and affinity, and can improve the water solubility, membrane permeability, and tumor targeting of traditional Protein Degraders.
- Dual-target Protein DegraderS
In the occurrence and development of cancer, there are usually a series of factors acting together, including different kinds of kinases and growth factors, which can act independently or interfere with each other through the signal network. The purpose of this method is to design a single molecule that combines two or more pharmacophores and targets two or more anti-tumor targets at the same time.
- Folate-caged Protein Degraders
Folate receptor alpha (FOLR1) is low in normal tissues but highly expressed in many human cancers. Folic acid cage Protein Degraders are another technique to improve the targeting specificity of Protein Degraders. Its basic principle is to introduce folic acid groups into Protein Degrader molecules and release them into target cells and tissues. In this technique, folic acid releases active Protein Degrader through the action of endogenous hydrolase, and then the degradation product induces the degradation of the target protein.
- TF-Protein Degraders
Transcription factors (TFs) are a kind of protein related to gene expression and regulation, and they are also a potential target for tumor therapy. Unlike traditional kinases, transcription factors do not have the active sites or allosteric regulatory sites common in kinases or other enzymes, so they are difficult to target by small molecular inhibitors. Because TFs can bind to specific DNA sequences and regulate the transcription process, different DNA sequences can be used instead of small molecular inhibitors to target TFs. Therefore, TF-Protein Degrader replaces the small molecular ligands of the targeted protein with the corresponding DNA sequence to form TF-Protein Degrader, which targets a specific TF and induces its degradation, thereby regulating the level of that specific TF and biological function.
Although Protein Degrader has developed rapidly in the past 20 years, there are still many challenges to be solved. These challenges mainly come from two aspects: the design and optimization of Protein Degrader molecules and the comprehensive evaluation of biological activities. The first is the molecular design and pharmacogenicity of Protein Degrader, involving target protein ligands, new E3 ligands, and a new linker. The second is biological activity evaluation, including Protein Degrader molecule screening, and drug and pharmacological evaluation. Although there are no ready answers to these challenges at present, it is expected that new evaluation methods and systems will be developed to solve these problems by conducting more research in biology, pharmacology, and clinical.