Degrader Building Blocks for Targeted Protein Degradation

Targeted Protein Degradation

An emerging strategy in drug discovery to access difficult-to-treat diseases is targeted protein degradation. While traditional small-molecule or antibody drugs may only allow access to ~20% of the proteome, degradation techniques may open the door to the other 80%.1 The molecules used in these approaches are often called protein degraders (such as proteolysis-targeting chimeras, or PROTAC® molecules), which are bifunctional molecules that eliminate target proteins from cells (Figure 1).1-5

*PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.

Targeted protein degradation via proteolysis-targeting chimeras (PROTACs)

Targeted protein degradation via proteolysis-targeting chimeras (PROTACs)

Figure 1. Targeted protein degradation via proteolysis-targeting chimeras (PROTACs)

 

PROTACs are designed with three primary components:

  1. A ligand at one end that targets the protein of interest (POI)
  2. A second ligand at the opposite end that binds an E3 ligase
  3. A crosslinker in the middle that joins the two ends (Figure 2).

The simultaneous PROTAC binding of two proteins brings the POI in close enough proximity for polyubiquitination by the E2 enzyme associated to the E3 ligase, which flags the POI for degradation through the proteasome.1-5

Learn more from Professor Alessio Ciulli in our recent webinar with the Royal Society of Chemistry: Targeted protein degradation using small molecules.

Degrader Building Blocks for Protein Degradation and PROTAC Research

The design of small molecules for target degradation is not trivial since even slight alterations in ligands and crosslinkers can affect binding to the POI or E3 ligase or the formation of the ternary complex.3-5 Thus, many analogs are synthesized – varying each structure slightly – and screened in cells to discover the optimal PROTAC or degrader for target degradation. To streamline this synthesis, our protein degrader building blocks are a collection of crosslinker-E3 ligase ligand conjugates with a pendant functional group for covalent linkage to a target ligand (Figure 2). Furthermore, because the same functional group is present across a series, one target ligand can be conjugated to several of our protein degrader building blocks in parallel for facile library generation and subsequent screening (Figure 3).

Degrader building blocks are permutations of the following components:

  • Ligands targeting the E3 ligase Cereblon (CRBN) or von Hippel–Lindau (VHL)
  • Crosslinkers with varied lengths and compositions
  • Conjugation sites with reactivity for common functional groups

PROTAC Synthesis

Figure 2. Primary components of PROTAC protein degraders

Advantages

  • Compatibility: Linkers conjugate to common functional groups present on target ligands.
  • Molecule design: Strategic variety encompassed in the combinations of linkers and ligands aids the design of target degraders.
  • Synthetic time-saver: The E3 ligand-crosslinker conjugates decrease the amount of time spent on PROTACs synthesis.
  • Library generation: Using degrader building blocks with the same conjugation site enables the simultaneous generation of several protein degraders via parallel synthesis.
Degrader building blocks simplify the synthesis of PROTAC protein degraders.
Use of a set of degrader building blocks with the same conjugation site streamlines the synthesis of libraries.

Figure 3. PROTAC Synthesis and PROTAC Library Generation

 

Please contact us for more information, bulk inquiries, or a full ChemDraw/sdf file of protein degrader building blocks and crosslinkers.

Materials

Catalog
Number
Products for CRBN Catalog
Number
Products for VHL
P0018 Pomalidomide 901490 (S,R,S)-AHPC hydrochloride
901494 N-Methylated Pomalidomide 901487 (S,S,S)-AHPC hydrochloride
901558 Lenalidomide 901534 (S,R,S)-AHPC-C6-CO2H
901500 Pomalidomide-C3-CO2H 901493 (S,R,S)-AHPC-PEG1-NH2 HCl
901496 Pomalidomide-C6-CO2H 901488 (S,R,S)-AHPC-PEG2-NH2 HCl
901525 Pomalidomide-C9-CO2H 901511 (S,R,S)-AHPC-PEG3-NH2 HCl
901527 Pomalidomide-PEG1-CO2H 901848 (S,R,S)-AHPC-PEG4-NH2 HCl
901526 Pomalidomide-PEG2-CO2H 901850 (S,R,S)-AHPC-PEG5-NH2 HCl
901504 Pomalidomide-PEG3-CO2H 901860 (S,R,S)-AHPC-PEG6-NH2 HCl
901824 Pomalidomide-PEG4-CO2H 906123 (S,R,S)-AHPC-PEG2-butyl amine hydrochloride
901828 Pomalidomide-PEG5-CO2H 905232 (S,R,S)-AHPC-C6-PEG3-Butyl-NH2 HCl
901829 Pomalidomide-PEG6-CO2H 905275 (S,R,S)-AHPC-PEG6-Butyl-NH2 HCl
901516 Pomalidomide-PEG1-NH2 HCl 901503 (S,R,S)-AHPC-PEG1-Alkyne
901513 Pomalidomide-PEG2-NH2 HCl 901517 (S,R,S)-AHPC-PEG2-Alkyne
901495 Pomalidomide-PEG3-NH2 HCl 901533 (S,R,S)-AHPC-PEG3-Alkyne
901830 Pomalidomide-PEG4-NH2 HCl 901851 (S,R,S)-AHPC-PEG4-Alkyne
901831 Pomalidomide-PEG5-NH2 HCl 901855 (S,R,S)-AHPC-PEG5-Alkyne
901832 Pomalidomide-PEG6-NH2 HCl 901873 (S,R,S)-AHPC-PEG6-Alkyne
905208 Pomalidomide-C6-PEG3-Butyl NH2 HCl 910538 (S,R,S)-AHPC-PEG2-butyl alkyne
905224 Pomalidomide-PEG6-Butyl NH2 HCl 910597 (S,R,S)-AHPC-PEG6-butyl alkyne
901523 Pomalidomide-PEG1-Alkyne 903957 (S,R,S)-AHPC-PEG1-Azide
901529 Pomalidomide-PEG2-Alkyne 904813 (S,R,S)-AHPC-PEG2-Azide
901531 Pomalidomide-PEG3-Alkyne 905216 (S,R,S)-AHPC-PEG2-Azide
901833 Pomalidomide-PEG4-Alkyne 904651 (S,R,S)-AHPC-PEG3-Azide
901834 Pomalidomide-PEG5-Alkyne 909262 (S,R,S)-AHPC-PEG4-Azide
901835 Pomalidomide-PEG6-Alkyne 909351 (S,R,S)-AHPC-PEG5-azide
910503 Pomalidomide-PEG2-butyl alkyne 909378 (S,R,S)-AHPC-PEG6-Azide
910511 Pomalidomide-C6-PEG3-butyl alkyne 904821 (S,R,S)-AHPC-C6-PEG3-Butyl Azide
910619
Pomalidomide-PEG6-butyl alkyne 905178 (S,R,S)-AHPC-C6-PEG1-C3-PEG1-Butyl Azide
903825 Pomalidomide-PEG1-Azide 904864 (S,R,S)-AHPC-PEG6-Butyl Azide
903833 Pomalidomide-PEG2-Azide 905399 (S,R,S)-AHPC-PEG2-Butyl Chloride
904678 Pomalidomide-PEG3-Azide 905380 (S,R,S)-AHPC-C6-PEG3-Butyl Chloride
909386 Pomalidomide-PEG4-Azide 905402 (S,R,S)-AHPC-C6-PEG1-C3-PEG1-butyl chloride
909394 Pomalidomide-PEG5-azide    
909408 Pomalidomide-PEG6-azide    
904872 Pomalidomide-PEG2-Butyl Azide    
903434 Pomalidomide-PEG6-Butyl Azide
904686 Pomalidomide-C6-PEG3-Butyl Azide
904880 Pomalidomide-C6-PEG1-C3-PEG1-Butyl Azide
904724 Pomalidomide-PEG2-Butyl Iodide
903442 Pomalidomide-PEG6-Butyl Iodide
904708 Pomalidomide-C6-PEG3-Butyl Iodide
906050 Pomalidomide-C6-PEG1-C3-PEG1-Butyl Iodide