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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Format: | Article |
Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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Series: | PLoS ONE |
Online Access: | https://doi.org/10.1371/journal.pone.0279063 |
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author | Chandru Gajendran Subramanyam Janardhan Tantry Naveen Sadhu M Zainuddin Mohammed Purushottam Dewang Mahanandeesha Hallur Sreekala Nair Krishnakumar Vaithilingam Basavaprabhu Nagayya Sridharan Rajagopal Dhanalakshmi Sivanandhan |
author_facet | Chandru Gajendran Subramanyam Janardhan Tantry Naveen Sadhu M Zainuddin Mohammed Purushottam Dewang Mahanandeesha Hallur Sreekala Nair Krishnakumar Vaithilingam Basavaprabhu Nagayya Sridharan Rajagopal Dhanalakshmi Sivanandhan |
author_sort | Chandru Gajendran |
collection | DOAJ |
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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format | Article |
id | doaj.art-f5b9a894f21344f3b3a771a2cac2103a |
institution | Directory Open Access Journal |
issn | 1932-6203 |
language | English |
last_indexed | 2024-04-09T23:43:16Z |
publishDate | 2023-01-01 |
publisher | Public Library of Science (PLoS) |
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series | PLoS ONE |
spelling | doaj.art-f5b9a894f21344f3b3a771a2cac2103a2023-03-18T05:32:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01181e027906310.1371/journal.pone.0279063Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer.Chandru GajendranSubramanyam Janardhan TantryNaveen Sadhu MZainuddin MohammedPurushottam DewangMahanandeesha HallurSreekala NairKrishnakumar VaithilingamBasavaprabhu NagayyaSridharan RajagopalDhanalakshmi SivanandhanDually 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.https://doi.org/10.1371/journal.pone.0279063 |
spellingShingle | Chandru Gajendran Subramanyam Janardhan Tantry Naveen Sadhu M Zainuddin Mohammed Purushottam Dewang Mahanandeesha Hallur Sreekala Nair Krishnakumar Vaithilingam Basavaprabhu Nagayya Sridharan Rajagopal Dhanalakshmi Sivanandhan Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer. PLoS ONE |
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 |
url | https://doi.org/10.1371/journal.pone.0279063 |
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