Reprogramming Aromatic Camptothecins into TOP1 Degraders via Synergistic Hydrophobic Tagging and Supramolecular Assembly

Aromatic camptothecins (CPTs) are clinically potent TOP1 inhibitors constrained by an “aromaticity–solubility” paradox, which leads to poor bioavailability and efflux-mediated resistance. Here, we report a modular strategy to reprogram the planar CPT scaffold into multifunctional topoisomerase I (TOP1) degraders by integrating hydrophobic tagging (HyT) with supramolecular self-assembly. Adamantane HyT introduces an orthogonal aliphatic module, converting classical inhibitors into proteasome-dependent degraders with enhanced membrane permeability while preserving TOP1-DNA binding affinity. This tag synergistically acts as a supramolecular anchor, enabling host–guest assembly with poly(β-cyclodextrin) to form stable, pH-responsive nanoparticles without pharmacophore modification. Our lead candidate, SN-38-A2, demonstrates potent TOP1 degradation and achieves superior tumor regression in xenograft models compared to clinical irinotecan. This synergistic HyT–supramolecular approach rebalances aromaticity for optimized drug-like properties, establishing a paradigm to transform solubility-limited warheads into high-performance degraders with integrated delivery.