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Linker Design and Optimization

With unparalleled expertise in the field of small molecule drug discovery, Creative Biolabs is fully competent and dedicated to offering one-stop PROTAC service which holds significant promise for exploring previously “undruggable” proteome in the area of drug discovery. To develop an efficient PROTAC, we offer our clients with molecule design service including ligand design for target protein, ligand screening for E3 ligase, as well as chemical linker design and optimization.

Background

To overcome the limitations of traditional therapeutic approaches for disordered proteins, PROteolysis TArgeting Chimera (PROTAC) was developed with selective manipulation of spatial and temporal disease-causing proteins. PROTAC degrades the target proteins at the post-translational level. Even though PROTAC owns promising therapeutic potential, it hasn't been broadly pushed into clinical trial stages. One of the key challenges is molecule discovery. For three components of PROTAC: a target-protein-binding moiety, a ligand for recruiting the degradation machinery, and a chemical linker, they are all critical for the efficiency of PROTAC. We already know that PROTACs with different chemical linker types, locations and lengths exhibit obviously different efficiencies for target degradation (see Fig.1). Herein, linker design and optimization may expand the PROTAC toolbox, and explore new possibilities for the broad application of PROTAC in various diseases.

Various linker types, lengths, and positions. Fig.1 Various linker types, lengths, and positions. (Zorba, 2018; Cyrus, 2010)

Introduction of Linker Design and Optimization

The PROTAC linker connects two functional heads: a ligand for E3 ligase recognition and a ligand for target protein recognition. It plays a vital role in efficient ubiquitination of the target protein and its ultimate degradation. To date, several kinds of linkers have been reported and applied in PROTAC ternary complexes formation, such as PEG linker, Alkyl linker, and “click chemistry” linker. In addition, linker length can be optimized by fine-tuning the distance between two participating partner proteins - target protein and E3 ligase to achieve maximal interaction. The length can be varied from 12-carbon to over 20-carbon. Furthermore, linker position can be optimized to determine various derivatizations to ensure a maximal binding affinity. Empowered by our advanced chemical molecule design and synthesis platform, Creative Biolabs offers our clients with linker design and optimization services based on different linker types, lengths, and positions.

Highlight Features of Our Services

  • From molecule design to evaluation
  • Experienced scientists and technicians
  • Maximum the success of every project
  • High efficiency and time-saving for you

To expand the broad application of PROTAC in a wide range of diseases, Creative Biolabs has explored a variety of methodologies in PROTAC design to investigate and develop an ideal PROTAC for our worldwide numerous clients. Both customized design/optimization and spot products are achievable in Creative Biolabs. To achieve the best efficacy, we do recommend our one-stop PROTAC design service. For more detailed information, please feel free to contact us and our team will get back to you as soon as possible.

Reference

  1. Zorba, A., et al. Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc Natl Acad Sci U S A. 2018, 115(31), E7285-E7292.
  2. Cyrus, K.; et al. Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. ChemMedChem. 2010, 5(7), 979-85.
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