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

Authors :
Lo CF
Chiu TY
Liu YT
Pan PY
Liu KL
Hsu CY
Fang MY
Huang YC
Yeh TK
Hsu TA
Chen CT
Huang LR
Tsou LK
Source :
Journal of medicinal chemistry [J Med Chem] 2022 Oct 13; Vol. 65 (19), pp. 12802-12824. Date of Electronic Publication: 2022 Sep 26.
Publication Year :
2022

Abstract

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
65
Issue :
19
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
36153998
Full Text :
https://doi.org/10.1021/acs.jmedchem.2c00631