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Article ; Online: Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer.

Chandru Gajendran / Subramanyam Janardhan Tantry / Naveen Sadhu M / Zainuddin Mohammed / Purushottam Dewang / Mahanandeesha Hallur / Sreekala Nair / Krishnakumar Vaithilingam / Basavaprabhu Nagayya / Sridharan Rajagopal / Dhanalakshmi Sivanandhan

PLoS ONE, Vol 18, Iss 1, p e

2023 Volume 0279063

Abstract: 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 ... ...

Abstract	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.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4.

Gajendran, Chandru / Fukui, Shoichi / Sadhu, Naveen M / Zainuddin, Mohammed / Rajagopal, Sridharan / Gosu, Ramachandraiah / Gutch, Sarah / Fukui, Saeko / Sheehy, Casey E / Chu, Long / Vishwakarma, Santosh / Jeyaraj, D A / Hallur, Gurulingappa / Wagner, Denisa D / Sivanandhan, Dhanalakshmi

Scientific reports

2023 Volume 13, Issue 1, Page(s) 3189

Abstract: Protein arginine deiminases (PAD) 4 is an enzyme that catalyzes citrullination of protein and its role in autoimmune diseases has been established through clinical genetics and gene knock out studies in mice. Further, studies with PAD4 - deficient mice ... ...

Abstract	Protein arginine deiminases (PAD) 4 is an enzyme that catalyzes citrullination of protein and its role in autoimmune diseases has been established through clinical genetics and gene knock out studies in mice. Further, studies with PAD4 - deficient mice have shown that PAD4 deficiency does not lead to increased infection or immune suppression, which makes PAD4 an attractive therapeutic target for auto-immune and inflammatory diseases. PAD4 has critical enzymatic role of promoting chromatin decondensation and neutrophil extracellular traps (NETs) formation that is associated with a number of immune-mediated pathological conditions. Here, we present a non-covalent PAD4 inhibitor JBI-589 with high PAD4 isoform selectivity and delineated its binding mode at 2.88 Å resolution by X-ray crystallography. We confirmed its effectiveness in inhibiting NET formation in vitro. Additionally, by using two mouse arthritis models for human rheumatoid arthritis (RA), the well-known disease associated with PAD4 clinically, we established its efficacy in vivo. These results suggest that JBI-589 would be beneficial for both PAD4 and NET-associated pathological conditions.
MeSH term(s)	Animals ; Humans ; Mice ; Arthritis, Rheumatoid/metabolism ; Extracellular Traps/metabolism ; Mice, Knockout ; Neutrophils/metabolism ; Protein-Arginine Deiminase Type 4/antagonists & inhibitors
Chemical Substances	Protein-Arginine Deiminase Type 4 (EC 3.5.3.15)
Language	English
Publishing date	2023-02-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-30246-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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