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  1. Article ; Online: 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

    2023  Volume 18, Issue 1, Page(s) e0279063

    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.
    MeSH term(s) Humans ; Cell Line, Tumor ; Histone Deacetylases/metabolism ; Histone Demethylases/genetics ; Neoplasms/drug therapy ; Histone Deacetylase 6
    Chemical Substances Histone Deacetylases (EC 3.5.1.98) ; Histone Demethylases (EC 1.14.11.-) ; HDAC6 protein, human (EC 3.5.1.98) ; Histone Deacetylase 6 (EC 3.5.1.98)
    Language English
    Publishing date 2023-01-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0279063
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. 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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  3. Article ; Online: Discovery and optimization of novel phenyldiazepine and pyridodiazepine based Aurora kinase inhibitors.

    Tamizharasan, Natarajan / Gajendran, Chandru / Kristam, Rajendra / Sulochana, Suresh P / Sivanandhan, Dhanalakshmi / Mullangi, Ramesh / Mathivathanan, Logesh / Hallur, Gurulingappa / Suresh, Palaniswamy

    Bioorganic chemistry

    2020  Volume 99, Page(s) 103800

    Abstract: Aurora B plays critical role in the process of chromosome condensation and chromosome orientation during the regulation of mitosis. The overexpression of Aurora B has been observed in several tumor types. As a part of our ongoing effort to develop Aurora ...

    Abstract Aurora B plays critical role in the process of chromosome condensation and chromosome orientation during the regulation of mitosis. The overexpression of Aurora B has been observed in several tumor types. As a part of our ongoing effort to develop Aurora B inhibitors, herein, we described the design, synthesis and evaluation of phenyl/pyridine diazepine analogs. The diazepane aniline pyrimidine (4a) was identified as an initial hit (Aurora B IC
    MeSH term(s) Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Aurora Kinase B/antagonists & inhibitors ; Aurora Kinase B/metabolism ; Azepines/chemical synthesis ; Azepines/chemistry ; Azepines/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug Screening Assays, Antitumor ; Humans ; Mice ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Structure-Activity Relationship
    Chemical Substances Antineoplastic Agents ; Azepines ; Protein Kinase Inhibitors ; AURKB protein, human (EC 2.7.11.1) ; Aurora Kinase B (EC 2.7.11.1)
    Language English
    Publishing date 2020-03-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120080-x
    ISSN 1090-2120 ; 0045-2068
    ISSN (online) 1090-2120
    ISSN 0045-2068
    DOI 10.1016/j.bioorg.2020.103800
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4207: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: A Novel Selective Inhibitor JBI-589 Targets PAD4-Mediated Neutrophil Migration to Suppress Tumor Progression.

    Deng, Hui / Lin, Cindy / Garcia-Gerique, Laura / Fu, Shuyu / Cruz, Zachary / Bonner, Erin E / Rosenwasser, Matthew / Rajagopal, Sridharan / Sadhu, M Naveen / Gajendran, Chandru / Zainuddin, Mohd / Gosu, Ramachandraiah / Sivanandhan, Dhanalakshmi / Shelef, Miriam A / Nam, Brian / Vogl, Dan T / Gabrilovich, Dmitry I / Nefedova, Yulia

    Cancer research

    2022  Volume 82, Issue 19, Page(s) 3561–3572

    Abstract: Neutrophils are closely involved in the regulation of tumor progression and formation of premetastatic niches. However, the mechanisms of their involvement and therapeutic regulation of these processes remain elusive. Here, we report a critical role of ... ...

    Abstract Neutrophils are closely involved in the regulation of tumor progression and formation of premetastatic niches. However, the mechanisms of their involvement and therapeutic regulation of these processes remain elusive. Here, we report a critical role of neutrophil peptidylarginine deiminase 4 (PAD4) in neutrophil migration in cancer. In several transplantable and genetically engineered mouse models, tumor growth was accompanied by significantly elevated enzymatic activity of neutrophil PAD4. Targeted deletion of PAD4 in neutrophils markedly decreased the intratumoral abundance of neutrophils and led to delayed growth of primary tumors and dramatically reduced lung metastases. PAD4-mediated neutrophil accumulation by regulating the expression of the major chemokine receptor CXCR2. PAD4 expression and activity as well as CXCR2 expression were significantly upregulated in neutrophils from patients with lung and colon cancers compared with healthy donors, and PAD4 and CXCR2 expression were positively correlated in neutrophils from patients with cancer. In tumor-bearing mice, pharmacologic inhibition of PAD4 with the novel PAD4 isoform-selective small molecule inhibitor JBI-589 resulted in reduced CXCR2 expression and blocked neutrophil chemotaxis. In mouse tumor models, targeted deletion of PAD4 in neutrophils or pharmacologic inhibition of PAD4 with JBI-589 reduced both primary tumor growth and lung metastases and substantially enhanced the effect of immune checkpoint inhibitors. Taken together, these results suggest a therapeutic potential of targeting PAD4 in cancer.
    Significance: PAD4 regulates tumor progression by promoting neutrophil migration and can be targeted with a small molecule inhibitor to suppress tumor growth and metastasis and increase efficacy of immune checkpoint blockade therapy.
    MeSH term(s) Animals ; Disease Models, Animal ; Extracellular Traps/metabolism ; Immune Checkpoint Inhibitors ; Lung Neoplasms/pathology ; Mice ; Neutrophils ; Protein-Arginine Deiminase Type 4 ; Receptors, Chemokine/metabolism
    Chemical Substances Immune Checkpoint Inhibitors ; Receptors, Chemokine ; Protein-Arginine Deiminase Type 4 (EC 3.5.3.15)
    Language English
    Publishing date 2022-11-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-21-4045
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma.

    Naveen Sadhu, M / Sivanandhan, Dhanalakshmi / Gajendran, Chandru / Tantry, Subramanyam / Dewang, Purushottam / Murugan, Kannan / Chickamunivenkatappa, Srinatha / Zainuddin, Mohd / Nair, Sreekala / Vaithilingam, Krishnakumar / Rajagopal, Sridharan

    Bioorganic & medicinal chemistry letters

    2020  Volume 34, Page(s) 127763

    Abstract: Lysine specific demethylase 1 (LSD1) and HDAC6 are epigenetic proteins associated with several diseases, including cancer and combined inhibition of these proteins could be highly beneficial in treating some cancers such as AML, MM and solid tumors. ... ...

    Abstract Lysine specific demethylase 1 (LSD1) and HDAC6 are epigenetic proteins associated with several diseases, including cancer and combined inhibition of these proteins could be highly beneficial in treating some cancers such as AML, MM and solid tumors. Multiple myeloma (MM) is a challenging cancer with fast relapse rate where novel treatment options are the need of the hour. We have designed and developed novel, LSD1 and HDAC6 selective dual inhibitors to target MM. Our dual inhibitor compound 1 shows superior potency in multiple MM cell lines. In MM.1S xenograft model compound 1 shows superior efficacy compared to single agent LSD1 and HDAC6 inhibitors by oral administration and is well tolerated. Further evaluation of the molecule in other cancers is in progress.
    MeSH term(s) Administration, Oral ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Histone Deacetylase 6/antagonists & inhibitors ; Histone Deacetylase 6/metabolism ; Histone Demethylases/antagonists & inhibitors ; Histone Demethylases/metabolism ; Humans ; Mice ; Molecular Structure ; Multiple Myeloma/drug therapy ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Structure-Activity Relationship
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-) ; HDAC6 protein, human (EC 3.5.1.98) ; Histone Deacetylase 6 (EC 3.5.1.98)
    Language English
    Publishing date 2020-12-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2020.127763
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3203: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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