Johanna Huchting, Fraunhofer ITMP, Hamburg

Targeted protein degradation (TPD) is a highly promising modality for novel therapeutics where, in contrast to traditional drugs that stoichiometrically inhibit protein function, molecular degraders catalytically deplete proteins of interest. Although hugely challenging for development, advanced TPD drug candidates mainly follow the modular design of the bRo5 hetero-bivalent PROTAC-prototype. Rational approaches for the discovery of monovalent molecular glue (MG)-type degraders are beginning to emerge; yet, clinical success for non-serendipitous MG degraders is still lagging behind.

At Fraunhofer ITMP, and with our partners in the PROXIDRUGS consortium, we are developing a versatile and multi-domain platform to identify molecular degraders for different targets in cell-based, screening-compatible assay formats. In addition, we are building informatics tools for integrated knowledge representation in the TPD field.

Here, we present our integrated platform approach PRISKA (PRoxidrugs Integrated Screening- and Knowledge-plAtform) through the lens of the androgen receptor as a validated anti-cancer target for TPD therapeutics. Modules of PRISKA comprise dedicated chemical libraries as well as assays that enable automated screening for protein degraders in 384-well plate format at high throughput. These include no-wash immunoassays highly specific for quantifying endogenous target protein, high-content imaging and positive selection setups. PRISKA integrated informatics module facilitates rational compound selection, screening analysis and refinement through different algorithms. Among them a knowledge graph that maps TPD actors (PROTACs, MGs, etc.), annotated through links to other public chemical biology data, as well as chemoinformatics tools aimed at identifying MG physicochemical features, thus allowing a fast filtering of virtual small molecule libraries for MG candidate probability.

Funding: This work is funded by the German Federal Ministry of Education and Research (BMBF) within the Cluster4Future PROXIDRUGS Grants No. 03ZU1109AA, 03ZU1109JA, 03ZU1109KB, 03ZU1109GB, 03ZU1109DB.