Breaking New Ground: Novel Preclinical Models for PROTAC Evaluation

Targeted protein degradation (TPD) is an emerging strategy designed to develop novel therapies for cancer and other diseases.
In recent years there has been significant interest in this field of drug discovery, and at the forefront of TPDs are proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MDGs) (Fig. 1). PROTACs are a novel class of heterobifunctional molecules that bind to both the E3 ligase and the target protein and contain three components; the protein of interest (POI) binding moiety, a linker, and E3 ubiquitin ligase binding moiety. Once bound, a ternary complex is formed (POI-PROTAC-E3 ligase), which hijacks the ubiquitin-proteosome system and is essential in driving proteasomal degradation of the target protein. Unlike conventional inhibitors that disable target proteins by direct binding, PROTACs are event-driven, meaning that a single PROTAC molecule can induce the degradation of multiple target protein molecules. This catalytic mechanism allows PROTACs to achieve complete inhibition of target proteins at lower concentrations compared to conventional inhibitors, making them a promising therapeutic approach for previously considered “undruggable” targets.

Using cost-efficient, high-throughout assays, ChemPartner has developed a comprehensive suite of preclinical models for
PROTAC evaluation, encompassing both in vitro and in vivo approaches. Using our range of validated assays, we can provide valuable insights into PROTAC efficacy, facilitating SAR studies and elucidating the relationship between molecular structure
and activity. Furthermore, our extensive in vivo capabilities facilitates the investigation of a PROTACs PK/PD profile, toxicity
and efficacy, providing a powerful tool accelerate PROTAC development whilst reducing the fail rate of PROTACs in clinical trials.

This poster will focus on a number of key assays that ChemPartner has validated from its PROTAC evaluation platform, which encompasses what we have defined as the “11 Key Questions for PROTACs”. Each question addresses a key aspect of a PROTAC’s biological activity or characteristics, thereby narrowing down the challenges in PROTAC SAR research.