Proximity-inducing substances (ProxiDrugs)

The aim of the platform is to make the drug class of proximity inducing drugs (PiDs) usable for the treatment of immune-mediated diseases. PiDs are bifunctional molecules which, by transient binding to two target structures, bring them into spatial proximity to each other and thereby trigger a biological effect. In PiDs in the narrow sense, one of the two structures is a ubiquitin E3 ligase, and the other is the target protein, which is tagged by this E3 ligase for degradation in the proteasome. These PiDs thus lead to the complete loss of the target protein with all its functions, e.g. catalytic, structural or regulatory, which distinguishes PiDs from classical inhibitors.

80% of the human proteome is considered »undruggable«

Despite a large arsenal of available drug classes, approximately 80% of the human proteome is considered therapeutically undruggable or difficult to access. An active site is not required for PiDs to act - making it possible to address disease-relevant target proteins previously considered undruggable.

PiDs, specifically PROTACs (proteolysis-targeting chimeras), are a new but intensively researched class of molecules. The most advanced compounds of this class are currently in the early stages of clinical development, mainly 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 efficacy tested in models of immuno-inflammatory diseases and their mode of action compared with that of classical inhibitors.

Coordinated inter-institutional collaboration as a basis

Experience and preliminary work on this class of therapeutics is currently limited within the Fraunhofer-Society, and there is no coordinated cross-institute collaboration on this topic. The PiD-Platform will use the established structures of the 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 Fraunhofer ITMP in the design, synthesis and optimization of active agents with the experience of Fraunhofer ISC in the development of three-dimensional human tissue models, the specialization of Fraunhofer ITEM in the field of relevant in vivo models of respiratory diseases and with the expertise of Fraunhofer IAP in the targeted glycosylation of biological active agents.

Outlook

For the development of the therapy platform, the individual tools and steps for the identification, characterization and optimization of PiDs will be developed and implemented on the basis of one or more selected target proteins. The cross-institutional collaboration should enable the development of robust high-throughput test systems in cell lines that are easy to culture and manipulate, as well as more complex, physiologically and pathophysiologically relevant model systems of human origin, predictive in vivo models and sophisticated analytical methods that allow the functional effect of PiDs in their target tissues and cells to be studied at the molecular level.

Currently, the application of PiDs is limited to oncological diseases. There are only a few molecules in clinical development and the mode of action of PiDs, for example compared 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 resulting from the combination of different binding sites for target proteins and E3 ligases. Depending on the E3 ligase recruited, the repertoire of degradable proteins and thus the specificity, efficacy and potential side effects of PiDs will vary.