PROTAC Brightens Disease Treatments: An Overview of the PROTAC Research, Challenges, and DMPK Solutions

Proteolysis-Targeting Chimera (PROTAC) * offers a new approach to some disease treatments and it has seen a boom in the last two years with Arvinas' two candidate molecules, ARV-110 and ARV-471, being the first to achieve positive clinical data. Many companies focusing on PROTAC development, such as Arvinas, Kymera Therapeutics and C4 Therapeutics, have made progress in PROTAC research, gaining access to pharmaceutical giants.

How does PROTAC work?

As a bifunctional molecule, PROTAC consists of three key structural parts: a ligand used to bind the target protein; a ligand binding the ubiquitin-protein ligase (E3); and a linker connecting the two ligands (Figure 1). 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.

Figure 1: Example of PROTAC structure

Why DMPK researches are so critical to PROTAC drug development

Notably, the development of PROTAC molecules still faces multiple challenges:

• It has high molecular weight, and poor solubility, and is difficult to meet the five principles of classical Lipinski.

• It has poor permeability in vivo and in vitro, leading to poor absorption and poor bioavailability.

• At high concentrations, a competitive formation of a target protein-PROTAC or E3 ligase-PROTAC binary complex occurs, leading to reduced efficacy.

• It shows high plasma protein binding in various species, slowing down its metabolism.

• Metabolite generation can lead to unpredictable protein degradation, resulting in loss of efficacy and even toxic reactions.

• There is no guidance specifically for PROTAC drugs.

The Strategy of the DMPK study for the PROTAC drug

Preclinical optimization of PROTAC drugs is mainly performed through cascade optimization of physicochemical and DMPK properties:

1. The first step is to characterize the in vitro properties of PROTAC molecules to conduct an initial screening.

2. In the optimization stage, the focus should be on improving the metabolic clearance and solubility of PROTAC, combined with the PK properties of extravascular drug delivery, to better understand the DMPK properties of PROTAC.

3. At the PCC stage, PROTAC molecules with potent and better oral bioavailability can be used in further PK/PD studies to obtain a more in-depth Exposure-response relationship.

WuXi AppTec DMPK expects more and more PROTAC molecules to be designed and developed, unlocking new opportunities in more disease areas, and bringing hope to more patients.

*PROTAC® is a registered trademark of Arvinas. In this article, PROTAC specifically refers to the abbreviation of Proteolysis-Targeting Chimera as therapeutic modalities.

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