RetroTAC: Learning Route-Derived Synthetic Accessibility for PROTACs

Proteolysis-targeting chimeras (PROTACs) enable targeted protein degradation, expanding therapeutic opportunities beyond conventional inhibition. However, assembling their large, multifunctional structures creates synthetic challenges that hinder their discovery. Traditional synthetic-accessibility scores can overestimate this difficulty by penalizing PROTACs' molecular complexity while overlooking modular assembly from accessible building blocks. In contrast, retrosynthesis planning tools provide explicit routes but are computationally expensive, particularly for large molecules. Here, we introduce a human-interpretable, PROTAC-oriented route-derived score that rewards short synthetic depth and balanced joining of molecular fragments, and RetroTAC, a machine-learning surrogate that predicts this score directly from molecular structures. RetroTAC combines complementary models in an ensemble, achieving a root mean squared error of 0.13 and an R squared of 0.65 on held-out molecules. We further evaluate its utility on PROTACs enumerated by recombining warheads, linkers, and E3-ligase ligands, followed by retrosynthetic planning and route analysis. Candidates selected for high predicted scores achieve a mean route-derived synthesizability of 0.73, compared with 0.31 for low-score candidates; 98.75% versus 51.00% are fully resolved under the tested search settings. These results support RetroTAC as a fast prioritization tool for virtual PROTAC libraries, connecting molecular screening with interpretable route characteristics while reserving explicit planning for selected candidates.