Structural and Physicochemical Features of Oral PROTACs

Area of Science:

• Medicinal Chemistry
• Pharmacokinetics
• Drug Discovery

Background:

• Achieving oral bioavailability for Proteolysis Targeting Chimeras (PROTACs) presents a significant hurdle in drug development.
• Existing drug development rules may not fully apply to the unique structural characteristics of PROTACs.

Purpose of the Study:

• To investigate the in vivo pharmacokinetic properties of oral PROTACs in preclinical species.
• To identify key molecular descriptors that correlate with oral bioavailability in PROTACs.
• To establish experimental guidelines for designing orally bioavailable PROTACs.

Main Methods:

• Evaluated pharmacokinetic profiles of four clinical oral PROTACs in mouse, rat, and dog models.
• Utilized Nuclear Magnetic Resonance (NMR) to determine 3D molecular conformations and preorganization.
• Introduced and quantified novel descriptors: solvent-exposed hydrogen bond donors (eHBD) and acceptors (eHBA).

Main Results:

• Established an upper limit of eHBD ≤ 2 for oral PROTACs in apolar environments.
• Demonstrated greater tolerance for other properties like eHBA, polarity, lipophilicity, and molecular weight compared to traditional oral drugs.
• Observed significantly lower oral bioavailability in PROTACs with eHBD > 2 compared to those with eHBD ≤ 2 within structurally related series.

Conclusions:

• Proposed an experimental "Rule-of-oral-PROTACs" to guide medicinal chemists.
• The eHBD descriptor is critical for achieving oral bioavailability in PROTAC design.
• This rule provides a practical framework for enhancing oral drug delivery of PROTAC therapeutics.