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Proteolysis targeting chimeras (PROTACs) have recently received significant attention as a new modality for therapeutic intervention.

PROTAC molecules are typically around 1 kDa in size, and often combine two (precursor) molecules with mediocre physicochemical properties (high log P, low solubility). As a result, the synthesis, analysis, and purification of these compounds can be more challenging than that for traditional small-molecule ligands.

Moreover, evidence is emerging that the linker plays the dominant role in PROTAC efficiency & selectivity, and we believe that a brute-force parallel approach to producing a large set of linkers will be key to PROTAC success.

To address these features, we have developed a modular chemistry toolbox, in which different linking strategies are combined with optimized analytical routines. We have

  1. A selection of E3 ligands (VHL, and a series of CRBN analogs),
  2. A set of alkyl and PEG linker with different length and composition
  3. Established chemistry to connect these linkers to the E3 ligands, using a variation of couplings
  4. Established chemistry to couple the linkers to the target ligand

This approach allows for the rapid assembly of a comprehensive set of different PROTAC molecules for any new target. Recently, we produced 20 PROTAC variants onto an NHR ligand, in less than two months! This used a matrix of CRBN, VHL, alkyl and PEG linkers of length 1 to 5 – very typical for a fast-track customer PROTAC project.

In addition, as part of our innovation activities, we are developing novel linkers that go beyond conventional polyethylene glycol (PEG) building blocks, with the goal of fine-tuning the properties of the resulting bivalent compound.

 

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