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

  • J Am Chem Soc. 2026 Jul 15;148(27):28342-28355. doi: 10.1021/jacs.6c03638.
Chunwei Shan  1  2 ,  Qian Chen  1  3 ,  Xixian Sun  1  2 ,  Shangjiu Hu  1 ,  Thulasiram Bathini  1 ,  Zijiang Yang  1  2 ,  Kaiming Chen  1 ,  Shan Mou  1  3 ,  Ruowen Wang  1  2 ,  Weihong Tan  1  4
Affiliations
  • 1. Institute of Molecular Medicine (IMM), Department of Nephrology, Molecular Cell Laboratory for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 2. College of Chemistry and Materials Science, Shanghai Normal University, 100 Guilin Road, Shanghai 200233, China.
  • 3. Department of Nephrology, Punan Branch of Renji Hospital, Shanghai Jiao TongUniversity School of Medicine, Shanghai 200125, China.
  • 4. Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences Medical School, University of Chinese Academy of Sciences, Zhejiang 310022, China.
PMID: 42378337 DOI: 10.1021/jacs.6c03638
Abstract

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.

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