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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Main Authors: Chandru Gajendran, Subramanyam Janardhan Tantry, Naveen Sadhu M, Zainuddin Mohammed, Purushottam Dewang, Mahanandeesha Hallur, Sreekala Nair, Krishnakumar Vaithilingam, Basavaprabhu Nagayya, Sridharan Rajagopal, Dhanalakshmi Sivanandhan
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2023-01-01
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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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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