Proteolysis-targeting chimeras (PROTAC®) acts as an important role in the area of target protein that is revolutionizing drug discovery. PROTAC®s drive protein degradation by simultaneously binding target proteins and E3 ligase and forming a productive complex. While the typical PROTAC®s are traditionally conceived as bifunctional which are composed of two ligands, novel trivalent PROTAC®s with an extra target protein binding site have shown more sustained and higher degradation efficacy. As a world-leading service provider in the field of drug research, Creative Biolabs can offer comprehensive trivalent PROTAC®s design, synthesis, and evaluation service to global clients based on our established platform. We guarantee to provide excellent service and competitive products to customers all over the world.
Fig.1 The ubiquitin-proteasome and typical divalent PROTAC®s.PROTAC®s have successfully been applied to degrade a wide spectrum of protein targets and shown satisfactory efficacy in multiple therapeutic areas, including oncology, inflammation, dermatology, immunology, and respiratory diseases. Typically bispecific PROTAC®s yield a productive ternary complex by inducing proximity between two proteins, which contribute to efficient ubiquitination. However, unfavorable PROTAC® ternary complexes and pronounced hook effects lead to slow and incomplete target degradation.
Similar to drug discovery, multivalent strategy also can be used in PROTAC®s design to enhance targeted protein degradation. Trivalent PROTAC®s are composed of bivalent target ligands and E3 ligase recruitment, which contains an extra target protein recognition site compared to traditional bivalent PROTAC® molecular. This added domain enhanced interaction activity to target proteins and enhance target degradation by mediating the formation of 1:1:1 complex with two target protein domains and a VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time, which led to more potent anticancer activity. Recent studies demonstrate that trivalent PROTAC®s have shown huge potential in the application of novel drug discovery.
Fig.2 Schematic illustration of BRD2 targeted Trivalent
PROTAC®s.As a newly developed method to enhance the potency of PROTAC®s, trivalent PROTAC®s attract more and more attention in the field of drug development, especially in anticancer therapeutic area. Recently, one group used BET domain family member proteins BRD2, BRD3, and BRD4 as model systems to design anticancer trivalent PROTAC®s. In this research, either VHL ligand or CRBN combined trivalent PROTAC®s have shown improved efficacy due to stronger binding activity. Moreover, trivalent PROTAC®s obtained an unexpected longer half-life than typical PROTAC®s and acceptable permeability. Furthermore, the remarkably favorable pharmacokinetics profile suggests that trivalent PROTAC®s will be appropriate for in vivo use. Meanwhile, scientists anticipate broad applicability of the approach to improve performance of a wide range of multispecific agents and modalities for chemical biology and pharmaceutical development.
Trivalent PROTAC®s provide an advanced strategy to design new PROTAC®s, which can be extended to the destruction of any protein of interest specifically and effectively. Based on the comprehensive and mature PROTAC® research platform, Creative Biolabs has launched one-stop trivalent PROTAC®s design, synthesis, and evaluation service to meet your requirement. If you are interested in our services, please directly contact us for more details.
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