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High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma

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...

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Autores principales: Ajay, Amrendra K., Chu, Philip, Patel, Poojan, Deban, Christa, Roychowdhury, Chitran, Heda, Radhika, Halawi, Ahmad, Saad, Anis, Younis, Nour, Zhang, Hao, Jiang, Xiuju, Nasr, Mahmoud, Hsiao, Li-Li, Lin, Gang, Azzi, Jamil R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10145398/
https://www.ncbi.nlm.nih.gov/pubmed/37111759
http://dx.doi.org/10.3390/pharmaceutics15041274
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author Ajay, Amrendra K.
Chu, Philip
Patel, Poojan
Deban, Christa
Roychowdhury, Chitran
Heda, Radhika
Halawi, Ahmad
Saad, Anis
Younis, Nour
Zhang, Hao
Jiang, Xiuju
Nasr, Mahmoud
Hsiao, Li-Li
Lin, Gang
Azzi, Jamil R.
author_facet Ajay, Amrendra K.
Chu, Philip
Patel, Poojan
Deban, Christa
Roychowdhury, Chitran
Heda, Radhika
Halawi, Ahmad
Saad, Anis
Younis, Nour
Zhang, Hao
Jiang, Xiuju
Nasr, Mahmoud
Hsiao, Li-Li
Lin, Gang
Azzi, Jamil R.
author_sort Ajay, Amrendra K.
collection PubMed
description 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.
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spelling pubmed-101453982023-04-29 High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma Ajay, Amrendra K. Chu, Philip Patel, Poojan Deban, Christa Roychowdhury, Chitran Heda, Radhika Halawi, Ahmad Saad, Anis Younis, Nour Zhang, Hao Jiang, Xiuju Nasr, Mahmoud Hsiao, Li-Li Lin, Gang Azzi, Jamil R. Pharmaceutics Article 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. MDPI 2023-04-18 /pmc/articles/PMC10145398/ /pubmed/37111759 http://dx.doi.org/10.3390/pharmaceutics15041274 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ajay, Amrendra K.
Chu, Philip
Patel, Poojan
Deban, Christa
Roychowdhury, Chitran
Heda, Radhika
Halawi, Ahmad
Saad, Anis
Younis, Nour
Zhang, Hao
Jiang, Xiuju
Nasr, Mahmoud
Hsiao, Li-Li
Lin, Gang
Azzi, Jamil R.
High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma
title High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma
title_full High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma
title_fullStr High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma
title_full_unstemmed High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma
title_short High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma
title_sort high-throughput/high content imaging screen identifies novel small molecule inhibitors and immunoproteasomes as therapeutic targets for chordoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10145398/
https://www.ncbi.nlm.nih.gov/pubmed/37111759
http://dx.doi.org/10.3390/pharmaceutics15041274
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