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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/...

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Autores principales: Gajendran, Chandru, Tantry, Subramanyam Janardhan, M., Naveen Sadhu, Mohammed, Zainuddin, Dewang, Purushottam, Hallur, Mahanandeesha, Nair, Sreekala, Vaithilingam, Krishnakumar, Nagayya, Basavaprabhu, Rajagopal, Sridharan, Sivanandhan, Dhanalakshmi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
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.
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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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