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Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer
Dually targeting the epigenetic proteins lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) that play a key role in cancer cells by modulating gene repressor complexes including CoREST will have a profound effect in inhibiting tumour growth. Here, we evaluated JBI-097 a dual LSD1/...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810167/ https://www.ncbi.nlm.nih.gov/pubmed/36595522 http://dx.doi.org/10.1371/journal.pone.0279063 |
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author | Gajendran, Chandru Tantry, Subramanyam Janardhan M., Naveen Sadhu Mohammed, Zainuddin Dewang, Purushottam Hallur, Mahanandeesha Nair, Sreekala Vaithilingam, Krishnakumar Nagayya, Basavaprabhu Rajagopal, Sridharan Sivanandhan, Dhanalakshmi |
author_facet | Gajendran, Chandru Tantry, Subramanyam Janardhan M., Naveen Sadhu Mohammed, Zainuddin Dewang, Purushottam Hallur, Mahanandeesha Nair, Sreekala Vaithilingam, Krishnakumar Nagayya, Basavaprabhu Rajagopal, Sridharan Sivanandhan, Dhanalakshmi |
author_sort | Gajendran, Chandru |
collection | PubMed |
description | Dually targeting the epigenetic proteins lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) that play a key role in cancer cells by modulating gene repressor complexes including CoREST will have a profound effect in inhibiting tumour growth. Here, we evaluated JBI-097 a dual LSD1/HDAC6 inhibitor, for its in vitro and in vivo activities in various tumor models. In vitro, JBI-097 showed a strong potency in inhibiting LSD1 and HDAC6 enzymatic activities with the isoform selectivity over other HDACs. Cell-based experiments demonstrated a superior anti-proliferative profile against haematological and solid tumor cell lines. JBI-097 also showed strong modulation of HDAC6 and LSD1 specific biomarkers, alpha-tubulin, CD86, CD11b, and GFi1b. In vivo, JBI-097 showed a stronger effect in erythroleukemia, multiple myeloma xenograft models, and in CT-26 syngeneic model. JBI-097 also showed efficacy as monotherapy and additive or synergistic efficacy in combination with the standard of care or with immune checkpoint inhibitors. These and other findings suggest that JBI-097 could be a promising molecule for targeting the LSD1 and HDAC6. Further studies are warranted to elucidate the mechanism of action. |
format | Online Article Text |
id | pubmed-9810167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-98101672023-01-04 Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer Gajendran, Chandru Tantry, Subramanyam Janardhan M., Naveen Sadhu Mohammed, Zainuddin Dewang, Purushottam Hallur, Mahanandeesha Nair, Sreekala Vaithilingam, Krishnakumar Nagayya, Basavaprabhu Rajagopal, Sridharan Sivanandhan, Dhanalakshmi PLoS One Research Article Dually targeting the epigenetic proteins lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) that play a key role in cancer cells by modulating gene repressor complexes including CoREST will have a profound effect in inhibiting tumour growth. Here, we evaluated JBI-097 a dual LSD1/HDAC6 inhibitor, for its in vitro and in vivo activities in various tumor models. In vitro, JBI-097 showed a strong potency in inhibiting LSD1 and HDAC6 enzymatic activities with the isoform selectivity over other HDACs. Cell-based experiments demonstrated a superior anti-proliferative profile against haematological and solid tumor cell lines. JBI-097 also showed strong modulation of HDAC6 and LSD1 specific biomarkers, alpha-tubulin, CD86, CD11b, and GFi1b. In vivo, JBI-097 showed a stronger effect in erythroleukemia, multiple myeloma xenograft models, and in CT-26 syngeneic model. JBI-097 also showed efficacy as monotherapy and additive or synergistic efficacy in combination with the standard of care or with immune checkpoint inhibitors. These and other findings suggest that JBI-097 could be a promising molecule for targeting the LSD1 and HDAC6. Further studies are warranted to elucidate the mechanism of action. Public Library of Science 2023-01-03 /pmc/articles/PMC9810167/ /pubmed/36595522 http://dx.doi.org/10.1371/journal.pone.0279063 Text en © 2023 Gajendran et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Gajendran, Chandru Tantry, Subramanyam Janardhan M., Naveen Sadhu Mohammed, Zainuddin Dewang, Purushottam Hallur, Mahanandeesha Nair, Sreekala Vaithilingam, Krishnakumar Nagayya, Basavaprabhu Rajagopal, Sridharan Sivanandhan, Dhanalakshmi Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer |
title | Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer |
title_full | Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer |
title_fullStr | Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer |
title_full_unstemmed | Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer |
title_short | Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer |
title_sort | novel dual lsd1/hdac6 inhibitor for the treatment of cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810167/ https://www.ncbi.nlm.nih.gov/pubmed/36595522 http://dx.doi.org/10.1371/journal.pone.0279063 |
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