An emerging strategy for difficult-to-treat diseases in drug discovery is targeted protein degradation. Creative Biolabs is a biopharmaceutical company dedicated to the development of protein degradation drugs for diseases such as cancer and autoimmune diseases, providing a new therapeutic strategy for the treatment of complex diseases. Our comprehensive capabilities and expertise in the fields of biology and chemistry enable us to perform all stage research on early drug development.

Overview of Protein Degraders

Proteolysis-targeting chimeras (Protein Degraders) have emerged as a new modality with the potential to revolutionize drug discovery. Protein Degraders are heterobifunctional molecules consisting of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a linker connecting the two ligands (Fig.1). The principle of Protein Degraders-mediated protein degradation strategy is based on ubiquitin-mediated proteolysis. Once the target: Protein Degraders: E3 ternary complex is formed, the E2 ubiquitin-conjugating enzymes transfer ubiquitin to lysine residues on the surface of the target protein. The recognition of the lysine polyubiquitination signal by proteasome promotes the subsequent degradation of the target protein.

Fig.1 Protein Degraders degrades target proteins by the ubiquitin-proteasome system. (An, 2018)

Ligand Design for Transcriptional Regulators Proteins

Most Protein Degraders have been designed against epigenetic targets, protein kinases, and nuclear receptors. Transcriptional regulatory proteins are involved in a large number of human diseases such as cancers, and they account for about 20% of all oncogenes identified to date. Therefore, there is a great need for these therapeutic molecules that can effectively modulate transcriptional activity. Protein Degraders, which target transcriptional regulators, can modulate their expression or degradation, or block protein/protein interactions, or prevent its DNA binding either through a binding pocket or at the DNA-interacting site to modulate protein transcription.

Creative Biolabs has a team of experienced experts with deep expertise in the fields of molecular discovery and synthetic chemistry. Our molecular discovery service supports the design of ligands for Protein Degraders that target multiple transcriptional regulatory proteins, including:

• Ligand Design for BRD4-targeting Protein Degraders
• Ligand Design for Sirt2-targeting Protein Degraders
• Ligand Design for HDAC6-targeting Protein Degraders
• Ligand Design for TRIM24-targeting Protein Degraders
• Ligand Design for IKZF1/3-targeting Protein Degraders
• Ligand Design for Smad3-targeting Protein Degraders

Creative Biolabs' ligand design services involve multiple target types, including nuclear receptors, protein kinases, regulatory proteins, cellular metabolic enzymes, fusion proteins, etc. Our services cover various fields of biopharmaceutical research and development, especially in the research focus areas such as cancer, infection, autoimmune diseases, diabetes, cardiovascular diseases, and neurodegenerative diseases. For more details, please feel free to contact us.

Reference

1. An, S.; Fu, L. Small-molecule Protein Degraders: An emerging and promising approach for the development of targeted therapy drugs. EBioMedicine. 2018, 36: 553-562.