Abstract
Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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B7-H1 Antigen / antagonists & inhibitors
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B7-H1 Antigen / genetics
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B7-H1 Antigen / metabolism*
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Binding Sites
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Breast Neoplasms / drug therapy
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Evaluation, Preclinical
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Female
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Humans
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Indoles / chemistry*
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Indoles / metabolism
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Indoles / pharmacology
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Indoles / therapeutic use
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Lymphocytes, Tumor-Infiltrating / cytology
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Lymphocytes, Tumor-Infiltrating / drug effects
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Lymphocytes, Tumor-Infiltrating / metabolism
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Mice
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Mice, Inbred BALB C
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Molecular Docking Simulation
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / metabolism*
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Protein Interaction Maps / drug effects
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Structure-Activity Relationship
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Thiazoles / chemistry*
Substances
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Antineoplastic Agents
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B7-H1 Antigen
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Indoles
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Programmed Cell Death 1 Receptor
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Thiazoles
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indoline