Are we ready to design oral PROTACs®?

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• PROTACs (proteolysis-targeting chimeras) represent a significant advancement in drug discovery, offering a novel therapeutic modality.
• The PROTAC-DB database serves as a primary resource for understanding the landscape of existing degraders.

Purpose of the Study:

• To statistically analyze the distribution of E3 ligases and protein of interest (POI) targets within PROTAC-DB.
• To develop a property-based design strategy for creating orally bioavailable PROTAC degraders.
• To define optimal chemical space regions for permeability and bioavailability.

Main Methods:

• Statistical analysis of E3 ligases and POIs in PROTAC-DB.
• Calculation of seven 2D descriptors for 2258 PROTACs and comparison with 50 orally approved drugs (bRo5).
• Construction of a chemical space using nC, PHI, and TPSA descriptors to identify favorable subregions.

Main Results:

• PROTAC-DB contains a diverse range of E3 ligases and POIs.
• Average PROTAC properties (MW, nC, NAR, PHI, nHDon, nHAcc, TPSA) were characterized.
• Optimal subregions within the defined chemical space were identified for oral degraders.
• Bioavailable PROTACs (ARV-110, ARV-471) were found closer to the bRo5 region, often utilizing semi-rigid linkers.
• Permeable PROTACs occupied a central chemical space region, with potential for chameleonicity.

Conclusions:

• PROTAC technology holds immense potential for future drug discovery.
• Property-based design strategies are crucial for developing orally administered PROTACs.
• Understanding the chemical space of PROTACs aids in optimizing pharmacokinetic properties like bioavailability and permeability.