Degraders early developability assessment: face-to-face with molecular properties

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Pharmacology

Background:

• Heterobifunctional small molecule degraders offer promise for treating diseases with unmet medical needs.
• Degrader molecules present challenges in cellular uptake and bioavailability due to their size and flexibility.
• Efficient property-based design is crucial for developing orally available degrader medicines.

Purpose of the Study:

• To investigate the applicability of established in silico tools for small molecule drug discovery to degrader molecules.
• To provide key physicochemical data (ionization, lipophilicity, polarity, chameleonicity) for a series of degrader compounds.
• To identify predictive models for degrader permeability.

Main Methods:

• Evaluated the transferability of standard in silico drug discovery tools to heterobifunctional degraders.
• Generated experimental data on ionization, lipophilicity, polarity, and chameleonicity for seven degrader compounds.
• Developed a model for predicting permeability using the experimental polarity descriptor Δlog k_W^IAM.

Main Results:

• Standard in silico tools used in small molecule drug discovery are not directly transferable to degrader design.
• Physicochemical properties including ionization, lipophilicity, polarity, and chameleonicity were characterized for seven degraders.
• Permeability of degraders can be effectively modeled using the experimental polarity descriptor Δlog k_W^IAM.

Conclusions:

• Ad hoc, property-based design strategies are essential for the discovery of new oral degrader drugs.
• The findings highlight the need for specialized approaches to overcome the unique challenges posed by degrader molecules.
• This work serves as a proof-of-concept for developing tailored design strategies in degrader drug discovery.