Proximity-inducing substances (ProxiDrugs)

The aim of the platform is to utilize the proximity-inducing drugs (PiDs) class of active ingredients for the treatment of immune-mediated diseases. PiDs are bifunctional molecules that transiently bind to two target structures, bringing them into proximity and thereby triggering a biological effect. In the case of PiDs in the narrower sense, one of the two structures is an ubiquitin E3 ligase, the other is the target protein, which is labelled by this E3 ligase for degradation in the proteasome. These PiDs thus lead to the complete loss of the target protein with all its catalytic, structure-giving or regulatory functions, which distinguishes PiDs from classical inhibitors.

80% of the human proteome is considered ‘undruggable’

Despite a large arsenal of available drug classes, about 80% of the human proteome is considered therapeutically inaccessible or difficult to access. An active site is not required for the effect of PiDs – this makes it possible to address disease-related target proteins that were previously considered undruggable.

PiDs, in particular PROTACs (proteolysis-targeting chimeras), are a new but very intensively researched class of molecules. The most advanced agents in this class are currently in the early phases of clinical development, primarily for oncological diseases.

Characterization and optimization of PiDs

The work within the platform is intended to establish the infrastructure, processes and workflows for the design, synthesis, characterization and optimization of PiDs in a cross-institutional collaboration. Two classes of PiDs will be addressed: PROTACS and LYTACs (lysosomal-targeting chimeras). Using one or more selected target proteins as examples, PiDs will be identified, their effectiveness tested in models of immune-inflammatory diseases and their mode of action compared with that of classic inhibitors.

Coordinated cross-institutional collaboration as a basis

The Fraunhofer-Gesellschaft currently has limited experience and preliminary work on this class of therapeutics, and there is no coordinated, cross-institutional collaboration on this topic. The PiD platform will use the established structures of CIMD to initiate such collaborations. In addition, the PiD platform will be closely networked with the PROXIDRUGS future cluster in the Rhine/Main area. 

The PiD platform combines the expertise of the Fraunhofer ITMP in the design, synthesis and optimization of active pharmaceutical ingredients with the experience of the Fraunhofer ISC in the development of three-dimensional human tissue models, the specialization of the Fraunhofer ITEM in the section of relevant in vivo models of respiratory diseases and with the expertise of the Fraunhofer IAP in the targeted glycosylation of biological active ingredients.

Outlook

For the development of the therapy platform, the individual tools and work steps for identifying, characterizing and optimizing PiDs are to be developed and implemented using one or more selected target proteins as examples. The cross-institutional collaboration should enable the development of robust high-throughput test systems in cell lines that are easy to cultivate and manipulate, as well as more complex, physiologically and pathophysiologically more relevant model systems of human origin, predictive in vivo models and sophisticated analytical methods that make it possible to examine the functional effect of PiDs in their target tissues and cells at the molecular level.

The use of PiDs is currently limited to oncological diseases. There are only a few molecules in clinical development and the mode of action of PiDs, for example in comparison to inhibitors of the same target proteins, is not yet fully understood. A major potential for the drug class lies in the almost inexhaustible modularity that results from the combination of different binding sites for target proteins and E3 ligases. Depending on the recruited E3 ligase, the repertoire of degradable proteins varies, as do the specificity, effect and potential side effects of PiDs. So far, only fewer than ten of the more than 600 known E3 ligases have binding modules that can be used to design PiDs. Many E3 ligases are expressed in a tissue-specific manner, and some are even preferentially expressed in diseased tissue. The development of ligands for these E3 ligases would enable the tissue- or cell-specific degradation of disease-related proteins.