Targeted Protein Degradation Platform (PROTACs)

An effective approach in drug discovery to access difficult diseases is Targeted Protein Degradation (TPD). TPD refers to the use of hetero-bifunctional small molecule "degraders" (e.g. PROTACs™) to achieve knockdown of target proteins within cells. Since its initial design by Sakamoto et al. in 2001, proteolysis-targeting chimera (PROTAC) technology has been successfully applied in the development of hetero-bifunctional molecules that can prompt target protein degradation. These hetero-bifunctional molecules generally consist of binding moieties for an E3 ubiquitin ligase and a target protein joined by a linker. The binding of both moieties results in the formation of a ternary complex between target protein and E3 ligase, leading to polyubiquitination of the target protein, its recognition by the proteasome and subsequent degradation. By removing target proteins directly rather than merely blocking them, protein degraders may provide multiple advantages over small molecule inhibitors. While traditional drugs may only allow access to ~20% of the proteome, TPD techniques may open the door to the other 80%.

(PROTAC is a registered trademark of Arvinas, Inc.)

Figure 1: Schematic showing the catalytic mode of action of heterobifunctional degrader molecules. Degraders initiate the formation of a ternary complex between an E3 ubiquitin ligase and a target protein which results in polyubiquitination of the target protein, its recognition by the proteasome and subsequent degradation. Degraders act catalytically by repeatedly engaging and directing the ubiquitination of target molecules.
(Adapted from Tinworth et al. 2016. Med.Chem.Comm. 7 2206.)

Advantages:

  • Compatibility: Linkers conjugate to common functional groups present on target ligands.
  • Flexibleolecule design: Strategic variety encompassed in the combinations of linkers and ligands aids the design of target degraders.
  • Synthetic time-saver: The E3 ligand-crosslinker conjugates decrease the amount of time spent on PROTACs synthesis.
  • Library generation: Using Partial PROTACs with the same conjugation site enables the simultaneous generation of several PROTACs via parallel synthesis.
  • Catalytic nature: PROTAC molecule can initiate another binding-degradation cycle after dissociation.

Peptide-Based PROTACs for TPD

Several oncoproteins, such as androgen receptor, estrogen receptor, ERRα, and BRD4, have been specifically ubiquitinated and destroyed via PROTACs, which function as bridges between the target protein and an E3 ligase. Peptide modulators exhibit greater potential than small-molecule drugs in several important aspects. Peptide modulators could significantly facilitate the modification of drugs and target protein−protein interactions, which are difficult to accomplish via small molecules.

BOC Sciences is specialized in the process development and the manufacturing of bioactive peptides. We are dedicated to offering services like custom peptide synthesis, process development, GMP manufacturing as well as catalog products for customers in both industry and academia.

Figure 2. Stabilized Peptide-Based PROTACs against Estrogen Receptor α (Adapted from Jiang Y. et al. ACS Chem. Biol. 2018, 13, 628−635.)

Our Services:

BOC Sciences provides a range of Protein Degraders (PROTAC molecules) targeting various protein targets, as well as Degrader Building Blocks, linkers and peptides to support TPD research and development.

While PROTAC technology has been a rising star in drug development in recent years, the technique is still facing some issues caused by relatively with high molecular weight, stability, toxicity, pharmacokinetics and bioavailability. By overcoming these limitations, PROTACs could be eventually developed as a novel class of drugs for the treatment of human diseases by targeted protein degradation. BOC Sciences will continue to investigate on this technique. We would be glad to hear from you and we’re looking forward to working with you.

Please find more PROTAC molecules on PROTAC.