Proteolysis Targeting Chimera (PROTAC) DMPK Services

Due to its unique structure, PROTAC induces E3 ligase to label the target protein with ubiquitin by bringing the E3 ligase and the target protein into proximity, promoting the degradation of the target protein, and the PROTAC molecules that fall off after the target protein degradation can continue to be recycled. Different from the occupancy drive pharmacology of most small molecule drugs, PROTAC can access previously inaccessible proteins without occupying an active pocket and relying on target occupancy to disrupt target protein, this is known as event-driven pharmacology.

The early DMPK evaluation of PROTAC molecules can be roughly divided into the following parts: One part is to characterize the basic DMPK properties of compounds, including the determination of physical and chemical properties, in vitro permeability detection, plasma protein binding and preliminary in vitro drug interaction tests. The other part is further screening optimization of compounds, focusing on the determination of solubility and in vitro metabolic properties (including qualitative and quantitative studies). The selected compounds will be advanced to in vivo PK studies in rodents to further evaluate the DMPK properties of the compounds.

Relevant technical guidelines for the safety evaluation of metabolites can also be applied to the evaluation of PROTAC molecules. If the relevant conditions are met, it is recommended to carry out toxicological evaluation of metabolites.

Whether poor permeability of PROTAC molecules in vitro predicts poor absorption in vivo has not been supported by a large amount of data. Our experience is that PROTAC molecules that show hypotonic in vitro may also achieve moderate bioavailability in animals, and therefore caution is recommended in the use of in vitro permeability data for screening PROTAC compounds. On the other hand, due to the characteristics of PROTAC molecules, there are many challenges in the in vitro testing of PROTACs (such as low solubility, strong non-specific adsorption, etc.), so it is also very important to select and optimize the relevant in vitro testing system for the study of PROTAC molecules.

PROTACs still belongs to the category of small molecule compounds, so it can follow the species selection method for the toxicology of small molecule compounds, that is, the principle of similarity between metabolism and human ancestry, while certain pharmacological effects are also need to be considered at the same time. Toxicological species of PROTAC do not always need to be monkeys.

In the early screening stage, in vivo PK studies in animals, it’s suggested to use clear solutions to avoid poor absorption due to solubility, and it is recommended to investigate the difference between fasted and fed exposure. Sometimes fed condition is conducive to oral absorption of PROTAC molecules. In terms of bioanalysis, attention should be paid to the non-specific adsorption of PROTAC molecules, low sample recovery and potential stability problems in the matrices.