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High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as
Amrendra K Ajay1,2, Philip Chu1, Poojan Patel1,2
1Transplant Research Centre, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Abstract:
Chordomas account for approximately 1-4% of all malignant bone tumors and 20% of primary tumors of the spinal column. It is a rare disease, with an incidence estimated to be approximately 1 per 1,000,000 people. The underlying causative mechanism of chordoma is unknown, which makes it challenging to treat. Chordomas have been linked to the T-box transcription factor T (TBXT) gene located on chromosome 6. The TBXT gene encodes a protein transcription factor TBXT, or brachyury homolog. Currently, there is no approved targeted therapy for chordoma. Here, we performed a small molecule screening to identify small chemical molecules and therapeutic targets for treating chordoma. We screened 3730 unique compounds and selected 50 potential hits. The top three hits were Ribociclib, Ingenol-3-angelate, and Duvelisib. Among the top 10 hits, we found a novel class of small molecules, including proteasomal inhibitors, as promising molecules that reduce the proliferation of human chordoma cells. Furthermore, we discovered that proteasomal subunits PSMB5 and PSMB8 are increased in human chordoma cell lines U-CH1 and U-CH2, confirming that the proteasome may serve as a molecular target whose specific inhibition may lead to better therapeutic strategies for chordoma.
Insights
Researchers screened 3730 compounds to find new chordoma treatments. Proteasomal inhibitors showed promise in reducing chordoma cell proliferation, suggesting the proteasome as a potential therapeutic target for this rare bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chordoma is a rare malignant bone tumor, comprising 1-4% of bone malignancies and 20% of primary spinal tumors.
- The causative mechanisms of chordoma remain largely unknown, hindering effective treatment development.
- The T-box transcription factor T (TBXT) gene has been implicated in chordoma development.
Purpose of the Study:
- To identify novel small molecules and potential therapeutic targets for chordoma treatment.
- To screen a library of compounds for activity against chordoma cells.
Main Methods:
- A small molecule library of 3730 unique compounds was screened.
- Hit compounds were evaluated for their efficacy in reducing human chordoma cell proliferation.
- Proteasomal subunit expression (PSMB5, PSMB8) was analyzed in chordoma cell lines.
Main Results:
- 50 potential hit compounds were identified, with Ribociclib, Ingenol-3-angelate, and Duvelisib as top candidates.
- A novel class of small molecules, including proteasomal inhibitors, demonstrated significant reduction in chordoma cell proliferation.
- Increased expression of proteasomal subunits PSMB5 and PSMB8 was observed in human chordoma cell lines (U-CH1, U-CH2).
Conclusions:
- Proteasomal inhibitors represent a promising new class of therapeutic agents for chordoma.
- The proteasome is a validated molecular target for developing novel chordoma treatment strategies.
- Targeted inhibition of the proteasome may offer improved therapeutic outcomes for chordoma patients.
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