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

Pharmaceutical scientists have huge expectations from heterobifunctional small molecule degraders to treat diseases with an unmet medical need. However, degraders are large and flexible and pose significant challenges in terms of cellular uptake and bioavailability. An efficient property-based design is therefore required to discover new oral degrader medicines. Here, we show the non-transferability to degraders of in silico tools routinely implemented in small molecule drug discovery programs; and provide ionization, lipophilicity, polarity and chameleonicity data for a series of seven degraders. We also reveal that permeability can be modeled by Delta log k(W)(IAM) - an experimental polarity descriptor. Overall, the paper is a proof-of-concept that shows to discover new oral degrader drugs ad hoc property-based design strategies are required.