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Updated: May 10, 2025
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Published on: May 2, 2025
Identification of Dinaciclib and Ganetespib as anti-inflammatory drugs using a novel HTP screening assay that targets
Shira Hagbi-Levi1, Michal Abraham2, Lika Gamaev1
1Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Introduction:
IFNγ plays both positive and negative roles in the regulation of innate and adaptive immune responses against tumors and virally infected tissues by upregulating CXCL10 and PD-L1 expression.
Methods:
To identify novel pathways and drugs that regulate the IFNγ-dependent PD-L1, we expressed GFP under the control of mouse PD-L1 promoter in mouse cancer cells that up regulate PD-L1 and CXCL10 in response to IFNγ stimulation. Using these cells, we screened an FDA approved library of 1496 small molecules known for their ability to inhibit IFNγ-dependent increase in PD-L1.
Results:
We identified 46 drugs that up regulated and 4 that down regulated IFNγ-dependent PD-L1 expression. We discovered that in addition to the known JAK inhibitors Ruxolitinib and Baricitinib, Dinaciclib, a CDK1/2/5/9 inhibitor, and Ganetespib, a Hsp90 inhibitor, significantly inhibit both PD-L1 and CXCL10 expression in the model cells. Furthermore, both drugs suppressed IFNγ-dependent CXCL10 and PD-L1 expression in-vitro in primary human lung cells and human cancer cells. These drugs also significantly inhibited delayed-type hypersensitivity (DTH) in-vivo in an inflammation mouse model.
Discussion:
Our novel screening platform can therefore be used in the future to identify novel immunomodulators and pathways in cancer and inflammation, expanding therapeutic horizons.
Insights
This study identifies novel drugs, including CDK and Hsp90 inhibitors, that regulate interferon-gamma (IFNγ)-dependent PD-L1 and CXCL10 expression. These findings offer new therapeutic strategies for cancer and inflammatory diseases.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Interferon-gamma (IFNγ) influences immune responses against tumors and viral infections by modulating CXCL10 and PD-L1 expression.
- Understanding the regulation of IFNγ-dependent PD-L1 is crucial for developing effective cancer immunotherapies.
Purpose of the Study:
- To discover novel pathways and drugs that regulate IFNγ-dependent PD-L1 expression.
- To establish a screening platform for identifying immunomodulators.
Main Methods:
- A screening platform using mouse cancer cells engineered to report IFNγ-dependent PD-L1 and CXCL10 upregulation was developed.
- An FDA-approved library of 1496 small molecules was screened for inhibitors of IFNγ-induced PD-L1.
Main Results:
- 46 drugs upregulated and 4 downregulated IFNγ-dependent PD-L1 expression.
- Dinaciclib (CDK inhibitor) and Ganetespib (Hsp90 inhibitor) significantly suppressed both PD-L1 and CXCL10 expression in vitro and in vivo.
- These drugs also inhibited delayed-type hypersensitivity (DTH) in a mouse model.
Conclusions:
- A novel screening platform for identifying immunomodulators was established.
- Dinaciclib and Ganetespib show potential as therapeutic agents for cancer and inflammatory conditions by modulating IFNγ signaling.
- The platform can be utilized to discover new immunomodulatory pathways and drugs.
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