Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design

Molecular glues are small molecules that offer a powerful strategy to target previously "undruggable" proteins of interest (POI) by enhancing their interactions with other proteins (effectors). Depending on the nature of the effectors, molecular glues can induce stabilizing sequestration or degradation of the POI. However, their rational design has been hindered by a poor understanding of how kinetic parameters impact their performance. To address this, we developed a unified mathematical framework that accurately represents the dynamics of both glue degraders and stabilizers in both in vitro and cellular contexts. By analyzing our model, we determined the effects of varying specific kinetic parameters on the cellular-level performance of molecular glues. Our model suggests that the binding affinity of the ternary complex is the key determinant of performance across both modalities, provided that the initial component concentrations and degradation rate constants are fixed. Furthermore, we demonstrated that degrader performance is ultimately limited by its catalytic efficiency and the target protein's natural half-life. We also identified distinct roles for effector abundance, showing that the relative concentrations of the effector and POI are critical for stabilizers but less so for degraders. This quantitative framework provides mechanistic principles for the rational design and optimization of molecular glues.