PROTAC Design

Let's discuss the components that make up a PROTAC in detail. First, we have the target ligand, which binds to the target protein that is to be degraded by the ligase. After the binding event, it brings both structures into close proximity, initiating the degradation of the target protein.

Ideally, the target ligand should be a potent and selective binder to the target structure. Often, in-house compounds are already sufficiently optimized or almost display desired physicochemical properties. For planning a PROTAC, it's crucial to identify the appropriate site on the molecule where it can be linked without interfering with the binding functionality (e.g., clashing with the macromoelcule surface).
If any predictions or PDBs are available, this information can be used to identify a suitable solvent-exposed position on the target ligand for attaching a linker. Otherwise, one has no choice but to resort to a trial-and-error approach to find an optimal position that does not significantly alter the ligand's affinity.

If the target ligand is already well-characterized, it can be advantageous to look for commercially available analogs that already contain a functional group that can easily be coupled with a linker. Chemical Spaces are well-suited for both purposes: to search for modified target ligands or for building blocks that can be synthesized into the target ligand through straightforward steps.

The ligase ligand offers somewhat less flexibility in design possibilities, but there are still options available. In addition to the well-known E3 ubiquitin ligase ligands like thalidomide, lenalidomide, and pomalidomide, there are also other structurally more complex entries.

A linker between the target ligand and the ligase ligand should always be attached at the correct position to avoid impairing the affinity to the binding partner. Once the positions are established, the next question is the type of linker. A PEG linker is commonly chosen due to its favorable formulation properties, increased water solubility, and the ease with which the optimal length can be sampled. The length of the linker is crucial for stabilizing the complex formed by the PROTAC, target, and ligase, which can vary depending on the target, protein class, and binding mode of the ligand.

From both an intellectual property and bioavailability perspective, it may also be beneficial to explore alternative linker modalities. Rigidification of the linker group can positively impact the pharmacological and pharmacokinetic behavior of the PROTAC and, through additional interactions in the complex, enhance the binding affinity of the PROTAC.

Chemical Spaces can be conveniently searched for ligase ligands with suitable functionalities for coupling, or directly for combinations of linkers and ligase ligands. A broader in-house arsenal provides efficient flexibility in projects and accelerates synthesis processes.