2. Academic Validation
  3. Trimethyl Lock-2Cl (TML-2Cl): A self-cyclizing adapter for molecular release in antibody-drug conjugates

Trimethyl Lock-2Cl (TML-2Cl): A self-cyclizing adapter for molecular release in antibody-drug conjugates

  • Eur J Med Chem. 2026 Mar 15:306:118640. doi: 10.1016/j.ejmech.2026.118640.
Xuzhuo Li 1,  Lizhe Bai 1,  Xiaomei Li 1,  Xing Jiang 2,  He Huang 3,  Yunyun Guo 4,  Jiahui Yu 1,  Shiliang Li 5,  Wei Lu 6,  Shulei Zhu 7
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.
  • 2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China; Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China.
  • 3 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China.
  • 4 ATLATL (Shanghai) Scientific Co., Ltd., 1077 Zhangheng Road, PuDong, Shanghai, PR China.
  • 5 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: [email protected].
  • 6 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China; Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: [email protected].
  • 7 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China; ATLATL (Shanghai) Scientific Co., Ltd., 1077 Zhangheng Road, PuDong, Shanghai, PR China. Electronic address: [email protected].
PMID: 41638011 DOI: 10.1016/j.ejmech.2026.118640
Abstract

The amide bond provides superior stability in chemical structures, enhances selectivity for drug loading, and reduces off-target toxicity during drug delivery. Conventional enzyme-cleavable antibody-drug conjugates (ADCs) typically rely on Cathepsin B-sensitive linkers conjugated to self-immolative spacers, such as p-aminobenzyl carbamate (PABC), p-aminobenzyl ether (PABE) spacers or ethylenediamine-derived motifs, to facilitate payload release. In this work, we introduced the trimethyl lock (TML) system as a versatile adapter to expand the scope of applicable payloads. To meet the PKA requirements of 1,6-elimination and subsequent rapid self-cyclization reactions, dichloro-modified trimethyl lock (TML-2Cl) was further developed and applied for the first time in drug delivery systems. Using Exatecan as the payload, hydrophilic and Cathepsin B-cleavable TML linker-payloads were designed and synthesized. Among these, L10081 and L10082, incorporating the hydrophilic units PSAR-10 or PEG-8, exhibited enhanced capacity for Exatecan release. Furthermore, the ADCs Her2-L10081 and Her2-L10082 significantly inhibited tumor growth in an NCI-N87 xenograft mouse model. However, although this adapter TML-2Cl exhibits excellent stability, its intrinsic hydrophobicity may limit its suitability for the development of ADCs with high drug-to-antibody ratios (DAR), particularly those incorporating poorly water-soluble payloads.

Keywords

Amide; Antibody-drug conjugates; Drug delivery; Exatecan; Trimethyl lock.

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