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- Title
Synthesis and Evaluation of Small Molecule Drug Conjugates Harnessing Thioester-Linked Maytansinoids.
- Authors
Lo, Chen-Fu; Chiu, Tai-Yu; Liu, Yu-Tzu; Huang, Li-Rung; Yeh, Teng-Kuang; Huang, Kuan-Hsun; Liu, Kuan-Liang; Hsu, Chia-Yu; Fang, Ming-Yu; Huang, Yu-Chen; Hsu, Tsu-An; Chen, Chiung-Tong; Tsou, Lun Kelvin
- Abstract
Ligand-targeting drug conjugates are a class of clinically validated biopharmaceutical drugs constructed by conjugating cytotoxic drugs with specific disease antigen targeting ligands through appropriate linkers. The integrated linker-drug motif embedded within such a system can prevent the premature release during systemic circulation, thereby allowing the targeting ligand to engage with the disease antigen and selective accumulation. We have designed and synthesized new thioester-linked maytansinoid conjugates. By performing in vitro cytotoxicity, targeting ligand binding assay, and in vivo pharmacokinetic studies, we investigated the utility of this new linker-drug moiety in the small molecule drug conjugate (SMDC) system. In particular, we conjugated the thioester-linked maytansinoids to the phosphatidylserine-targeting small molecule zinc dipicolylamine and showed that Zn8_DM1 induced tumor regression in the HCC1806 triple-negative breast cancer xenograft model. Moreover, in a spontaneous sorafenib-resistant liver cancer model, Zn8_DM1 exhibited potent antitumor growth efficacy. From quantitative mRNA analysis of Zn8_DM1 treated-tumor tissues, we observed the elevation of gene expressions associated with a "hot inflamed tumor" state. With the identification and validation of a plethora of cancer-associated antigens in the "omics" era, this work provided the insight that antibody- or small molecule-based targeting ligands can be conjugated similarly to generate new ligand-targeting drug conjugates.
- Subjects
TRIPLE-negative breast cancer; LIGAND binding (Biochemistry); BINDING site assay; ANTINEOPLASTIC agents; LIVER cancer
- Publication
Pharmaceutics, 2022, Vol 14, Issue 7, pN.PAG
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics14071316