Synthesis and Evaluation of Small Molecule Drug Conjugates Harnessing Thioester-Linked Maytansinoids
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 prematur...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Book |
| Published: |
MDPI AG,
2022-06-01T00:00:00Z.
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| Subjects: | |
| Online Access: | Connect to this object online. |
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| Summary: | 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 <b>Zn8_DM1</b> induced tumor regression in the HCC1806 triple-negative breast cancer xenograft model. Moreover, in a spontaneous sorafenib-resistant liver cancer model, <b>Zn8_DM1</b> exhibited potent antitumor growth efficacy. From quantitative mRNA analysis of <b>Zn8_DM1</b> 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. |
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| Item Description: | 10.3390/pharmaceutics14071316 1999-4923 |