E3 Ligases are important components of the Ubiquitin Proteasome System (UPS). As the master regulator of protein homeostasis, UPS is essential in signal transduction, mitophagy, DNA damage repair, inflammatory pathways, endocytosis and cell-cycle progression. More than 600 E3 ligases have been discovered, and only a few of these have been used in PROTAC designs. The development of anti-cancer PROTAC mainly uses the ligands of CRBN, VHL, MDM2, IAPS, dCAF15, dCAF16, RNF4 and RNF114 E3 ligases.
Figure 1. Distribution of E3 ligases in normal tissues
Most PROTACs developments utilize ligands that recruit E3 ligases, which is widely expressed in tumors and normal tissues, and these PROTACs can cause off-target toxicity if the target protein of interest is not tumor-specific. The identification of those E3 ligase that are enriched in tumors but very low in normal tissues will facilitate the development of tumor-specific/selective PROTACs.
As an experienced service provider in biological research and drug discovery, Profacgen provides E3 ligase development including single-subunit E3 ligases, multi-subunit E3 ligase complexes, tissue specific E3 ligases, and other target proteins development services. With the comprehensive advanced platform, Profacgen offers our clients a one-stop PROTAC development services. Please feel free to contact us for more information.
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3. Sajid Khan, Yonghan He et al. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene 2020, 4909-4924. doi: 10.1038/s41388-020-1336-y
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