4.7 Article

Targeting the Phosphatidylserine-Immune Checkpoint with a Small-Molecule Maytansinoid Conjugate

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 19, Pages 12802-12824

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00631

Keywords

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Funding

  1. National Health Research Institutes
  2. Ministry of Economic Affairs of the Republic of China (MOEA)
  3. [106 -EC -17-A-22-1099]

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This study reports a small molecule-based immune checkpoint-targeting drug delivery system, which shows great potential for cancer treatment. The system not only inhibits tumor growth effectively, but also improves the immunosuppressive tumor microenvironment, leading to enhanced therapeutic efficacy.
Ligand-targeting drug delivery systems have made significant strides for disease treatments with numerous clinical approvals in this era of precision medicine. Herein, we report a class of small molecule-based immune checkpoint-targeting maytansinoid conjugates. From the ligand targeting ability, pharmacokinetics profiling, in vivo anti-pancreatic cancer, triple-negative breast cancer, and sorafenib-resistant liver cancer efficacies with quantitative mRNA analysis of treated-tumor tissues, we demonstrated that conjugate 40a not only induced lasting regression of tumor growth, but it also rejuvenated the once immunosuppressive tumor microenvironment to an inflamed hot tumor with significant elevation of gene expressions that were not accessible in the vehicle-treated tumor. In turn, the immune checkpoint-targeting small molecule drug conjugate from this work represents a new pharmacodelivery strategy that can be expanded with combination therapy with existing immune-oncology treatment options.

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