CupOFLATTE: Coupled Objective-Guided Discrete Flows via Linker Assembly for Targeted PROTAC Engineering

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules whose function emerges from three coupled components: a warhead that binds a protein of interest, a linker, and an E3 ligand that recruits the cellular degradation machinery. Most generative approaches design the linker in isolation and assemble the ternary molecule only after generation, ignoring cross-component dependencies and often producing PROTACs that fall outside the empirical degrader distribution. We introduce Coupled Objective-Guided Discrete Flows via Linker Assembly for Targeted proTac Engineering (CupOFLATTE), a discrete generative framework that restricts generative trajectories to a chemically feasible conjugate manifold and biases local transitions using soft objectives derived from PROTAC-DB chemistry, keeping warhead, linker, and E3 ligand components compatible throughout generation. Across assembly validity, predicted degradation activity (DegradeMaster), and PROTAC-like physicochemical property ranges, CupOFLATTE outperforms staged baselines including LinkerNet, DiffLinker, and DiffPROTACs, demonstrating that explicit coupling and constraint enforcement are sufficient to recover functional degraders in settings where function emerges only at the level of the assembled ternary system.