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PROTAC Synthesis & Screening for Targeted Protein Degradation

We have extensive experience in the synthesis of Proteolysis Targeting Chimeras (PROTAC) and partial PROTAC for targeted protein degradation, including the development and functionalization of various E3-ligase ligands such as CRBN, VHL, MDM2 ,and cIAP1, some of them even in multi-gram scale. In addition to the synthesis of commercially available ligands, we are also experienced in developing novel structural analogues.

Protac Synthesis 1
 

Our PROTAC synthesis and screening services for targeted protein degradation include:

 
  • Synthetic capability to rapidly progress from milligram to gram scale and beyond
  • Capability to develop novel linkers for discovery needs
  • Experience in homo PROTACs and partial PROTACs and SNIPERs
  • Capability of optimizing the NCEs for potency and better physicochemical properties
  • In-house library of partial PROTACs and linkers for rapid target engagement
  • Chemistry and integrated discovery support
  • Stand-alone biology support including in vitro and in vivo profiling, DMPK, or toxicology

We also synthesize a large variety of linkers needed for the linkage of E3-Ligase ligands to the target-binding ligands, including PEG linkers, carbon-based chains, with a large variety of end functionalities including –NH2, –CO2H, –N3, –C≡CH, –CHO, –X and –OH to be connected with almost any active targets.

Protac Synthesis 2

We have unique capabilities for tailor-made partial PROTACs, which are ready for rapid target linkage. We also have a series of E3-ligase ligands and linkers on our shelves.

Protac Synthesis 3
 

Our in-house collection offers clients a quick and efficient way to jump-start their drug discovery programs and reach meaningful conclusions faster.

We complement our medicinal chemistry of PROTACs with a vast experience in the biology of protein degraders and comprehensive in vitro biology support, including various biological assays, DMPK and toxicology support.

 

Our discovery biology expertise for PROTAC screening includes:

 
  • TR-FRET assays for biochemistry (EnVision XCite)
  • Cell-based assays for evaluating target degradation (Hi-Bit, Nano-Bit etc.) including calculation of DC50 values
  • Preliminary ADME studies (e.g. permeability, solubility, microsomal stability)
  • PK studies in rodents
  • Xenograft studies and other PD models
  • Toxicology studies
  • Analysis of ternary complexes

FAQ

Target Protein degradation is a process in which the protein of interest is degraded using E3 ubiquitin ligase and a chemical linker by polyubiquitination followed by proteasome degradation.

High target selectivity demonstrates high potencies, less toxic ,and minimizing the risk of developing resistance.

A targeting ligand (warhead) for the protein of interest and a ligand that recruits an E3 ubiquitin ligase connected via a carefully-chosen chemical linker (PROTAC). The resulting compound can induce formation of a ternary complex (the target, degradation compound and E3 ligase). The design of degrader compounds is critical to form an effective ternary complex.

The addition of ubiquitin to a substrate protein is called ubiquitination. Ubiquitination of target proteins involves a three-step enzymatic process, i.e., Activation, conjugation, and Ligation. Finally, polyubiquitinated proteins are recognized by the proteasome then degrades into small peptides by proteolysis.

Cellular Permeability and Target Affinity are the important factors to decide the effective binding of PROTAC with target protein and ubiquitination. These parameters play a crucial role in the designing of PROTAC molecules.

PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance of affecting nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. It has attracted great attention both from academia and industry.

Catalytic in nature, targeted degradation and selectivity provide a niche for PROTAC applications in cancer diseases and immune disorders, viral infections, and neurodegenerative diseases.

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