Limiting Trial-and-Error: Linker-Based 2D Descriptor Analysis to Support Very Early Proteolysis-Targeting Chimeras...

Targeted protein degradation has emerged as a clinically validated therapeutic strategy, culminating in the recent FDA approval of the first proteolysis-targeting chimeras (PROTAC) drug (VEPPANU). Within PROTACs, the linker plays a central role in modulating degradation efficiency as well as physicochemical and in vitro absorption, distribution, metabolism, and excretion properties, yet linker optimization still largely relies on empirical "linkerology" approaches. Here, we investigated whether simple 2D linker descriptors could provide informative insights for very early-stage PROTAC design. Four matched PROTAC series, including both cereblon- and von Hippel-Lindau-recruiting degraders, were retrospectively analyzed using a workflow combining the in-house Bellerophon-based linker extraction with principal component analysis. Selected descriptors captured linker hydrophobicity, polarity, flexibility, and topology and were correlated with experimental degradation, permeability, solubility, lipophilicity, protein binding, and metabolic stability data. In several datasets, linker-dependent trends associated with the molecular properties of degraders and their degradation efficiency were identified, particularly for von Hippel-Lindau-based PROTACs. Although the limited size of currently available datasets prevents broad generalization, this work highlights the potential of simple descriptor-based analyses to support early candidate prioritization and reduce unnecessary synthetic efforts.