Targeted protein degradation combats the therapeutic limit of small molecules by overcoming drug resistance and uncoupling their pharmacokinetics from pharmacodynamics, providing a new strategy for the treatment of difficult-to-cure diseases. Creative Biolabs has an advanced protein degradation platform-PROTAC®, and we can provide one-stop molecular discovery services for customers all over the world to produce PROTAC® that can effectively degrade target proteins that cause diseases.
Targeted protein degradation is a new modality of chemical biology and drug discovery. PROTAC® is a technology that uses the ubiquitin-protease system to target a specific protein and induces its degradation in the cell. PROTAC® is a bifunctional molecule, which consists of three parts: a ligand for binding target protein of interest, a ligand for recruiting E3 ligase and a linker connecting the two ligands. Once the ternary complex (target-PROTAC®-E3) is formed, the recruited E3 will employ an E2 ubiquitin-conjugating enzyme to transfer ubiquitin to the target protein surface. The proteasome will recognize polyubiquitination signals to promote the degradation of the target protein. PROTAC® has the potential to eliminate the “undruggable” proteome that comprises about 85% of human proteins, suggesting that it has great prospects in the therapeutic field.
Fig.1 Schematic diagram of PROTAC®. (a) The composition of PROTAC®. (b) Mechanism of action of PROTAC®. (Gu, 2018)
TRIM24 is a multidomain protein that has been considered to be a co-regulator of transcription. It is a member of the TRIM/ RBCC protein family, defined by a conserved amino-terminal tripartite motif and variable carboxy-terminal domains. The RING domain of TRIM24 is involved in the ubiquitination and degradation of the transcription factor, p53 and the conserved LxxLL motif is associated with co-activation or co-repression of nuclear receptors. Recently, TRIM24 has been implicated as a dependency in numerous cancers, such as breast and prostate cancers. Studies have found that high levels of TRIM24 are related to tumorigenesis and disease progression in a variety of cancer lineages. Besides, the TRIM24 gene knockdown has been associated with impaired cell growth and induction of apoptosis.
PROTAC® technology is a powerful tool to induce the degradation of various proteins. In 2018, the Bradner group developed a PROTAC®, dTRIM24, to degrade TRIM24 by the recruitment of the VHL E3 ubiquitin ligase. The degrader caused effective and selective degradation of TRIM24 with a maximum degradation at 5 µM. The study of TRIM24 degradation versus bromodomain inhibition has shown that the anti-proliferative response from degradation is enhanced. As a result, dTRIM24 provided a chemical probe of an emerging cancer dependency and established a path forward for the treatment of difficult-to-treat diseases.
In order to target a wider range of proteins with higher specificity, PROTAC® has gradually become a promising technology in the development of therapeutics. For the design and development of PROTAC®, proper ligand design is very important to determine the specificity of PROTAC®. Creative Biolabs provides ligand design services for target proteins to ensure efficient PROTAC® molecules, the ligands can be several different forms, such as small molecules, peptides, proteins, as well as antibodies. In addition, we also provide other related services to improve PROTAC®'s poor stability and penetrability, including structural modification, ligand screening for E3 ligase, and optimization of linker length and position, etc.
By removing target proteins directly rather than merely blocking them, PROTAC® technology shows multiple advantages over small-molecule inhibitors, including
Creative Biolabs is your preferred partner for drug discovery. Applying deep expertise from an experienced team of experts, we can assist our clients to obtain the best PROTAC® molecules. If you want more details, please feel free to contact us.
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