E3 Ligase/Target Protein Development

Abnormal protein expression or activities are closely associated with many diseases, especially cancer. Therefore, down-regulating the targeted proteins is an effective strategy to treat diseases. Recently, a series of targeted protein degradation methods have been developed by using small molecules. PROTAC technology has also risen as a powerful tool to degrade target proteins by hijacking the ubiquitin-proteasome system that includes E3 ligases. Many drugs based on the PROTAC mechanism have shown clinical efficacy. Here, Profacgen provides a broad range of services for discovering, producing, and engineering E3 ligases and target proteins.

Target proteins are usually the proteins whose overexpression or accumulation may play an important role in the occurring of diseases. Many PROTACs have been developed to degrade the target proteins, including kinases (such as CDK, KARS, MEK, and Bcr/Abl). Transcription factors (such as p53, STAT, RAR, ER, and AR), epigenetic tools (such as HDAC and BET bromodomain), and E3 ligase themselves (such as MDM2).

A ubiquitin ligase (also called E3 ligase) can recruit an E2 ubiquitin-conjugating enzyme that is loaded with ubiquitin, recognize a protein substrate, and help catalyze the ubiquitin transferring from E2 to the protein substrate. There are approximately 500-1,000 E3 ligases in human cells. Still, only a few have been identified and used for PROTACs, which include Von Hippel-Lindau disease tumor suppressor protein (VHL), the Cellular Inhibitor of Apoptosis (cIAP), the Mouse Double Minute 2 Homologue (MDM2), and ereblon (CRBN).

Figure 1. Ternary complex of PROTAC with POI and E3 ligase

With the integrated resources, Profacgen is happy to help with the expression, purification, and modification of both E3 ligases and target proteins.

Our services include but are not limited to:

• Protein labeling
• Custom protein ubiquitination
• Novel E3 ligase discovery
• Protein expression and purification
• Protein engineering

Our advantages:

• Integrated in silico and experimental services
• Highly efficient protein production services
• Custom protein engineering service
• Detailed report with results and analysis

Please contact us for more details. We are more than happy to generate a tailored proposal for you based on the specific requirements.

References:

[1] Cermakova, K.; Hodges, H.C. Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation. Molecules 2018, 23, 1958.

[2] Wang Y, Jiang X, Feng F, Liu W, Sun H. Degradation of proteins by PROTACs and other strategies. Acta Pharm Sin B 2020;10: 207e38.