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  1. Article ; Online: A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells.

    Auvin, Serge / Öztürk, Harun / Abaci, Yusuf T / Mautino, Gisele / Meyer-Losic, Florence / Jollivet, Florence / Bashir, Tarig / de Thé, Hugues / Sahin, Umut

    Life science alliance

    2019  Volume 2, Issue 4

    Abstract: Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen-androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive ... ...

    Abstract Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen-androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects' importance in modulating drug activity in vivo.
    MeSH term(s) Androgen Antagonists/metabolism ; Androgen Receptor Antagonists/metabolism ; Androgen Receptor Antagonists/pharmacology ; Androgens/metabolism ; Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/drug effects ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Prostate/metabolism ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Receptors, Androgen/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
    Chemical Substances Androgen Antagonists ; Androgen Receptor Antagonists ; Androgens ; Receptors, Androgen
    Language English
    Publishing date 2019-08-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2575-1077
    ISSN (online) 2575-1077
    DOI 10.26508/lsa.201800213
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein.

    Lama, Dilraj / Liberatore, Anne-Marie / Frosi, Yuri / Nakhle, Jessica / Tsomaia, Natia / Bashir, Tarig / Lane, David P / Brown, Christopher J / Verma, Chandra S / Auvin, Serge

    Chemical science

    2019  Volume 10, Issue 8, Page(s) 2489–2500

    Abstract: Stapled-peptides have emerged as an exciting class of molecules which can modulate protein-protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and ... ...

    Abstract Stapled-peptides have emerged as an exciting class of molecules which can modulate protein-protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions. This recognition element is a major molecular determinant underlying the improved binding kinetics of these peptides with eIF4E. The interactions were further exploited by designing features in the peptides to attenuate disorder and increase helicity which collectively resulted in the generation of a distinct class of hydrocarbon stapled-peptides targeting eIF4E. This study details new insights into the molecular basis of stapled-peptide: eIF4E interactions and their exploitation to enhance promising lead molecules for the development of stapled-peptide compounds for oncology.
    Language English
    Publishing date 2019-01-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 2559110-1
    ISSN 2041-6539 ; 2041-6520
    ISSN (online) 2041-6539
    ISSN 2041-6520
    DOI 10.1039/c8sc03759k
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Novel azoles as potent and selective cannabinoid CB2 receptor agonists.

    Harnett, Jeremiah J / Dolo, Christine / Viossat, Isabelle / Auger, Florence / Ferrandis, Eric / Bigg, Dennis / Auguet, Michel / Auvin, Serge / Chabrier, Pierre-E

    Bioorganic & medicinal chemistry letters

    2015  Volume 25, Issue 1, Page(s) 88–91

    Abstract: Novel azole compounds were prepared which demonstrated potent hCB2 binding activities with antioxidant activity for a selected compound. These compounds show good selectivity over the hCB1 receptor and are full agonists at the hCB2 receptor. ...

    Abstract Novel azole compounds were prepared which demonstrated potent hCB2 binding activities with antioxidant activity for a selected compound. These compounds show good selectivity over the hCB1 receptor and are full agonists at the hCB2 receptor.
    MeSH term(s) Animals ; Azoles/chemistry ; Azoles/metabolism ; CHO Cells ; Cannabinoid Receptor Agonists/chemistry ; Cannabinoid Receptor Agonists/metabolism ; Cannabinoids/chemistry ; Cannabinoids/metabolism ; Cricetinae ; Cricetulus ; Humans ; Receptor, Cannabinoid, CB2/agonists ; Receptor, Cannabinoid, CB2/metabolism
    Chemical Substances Azoles ; Cannabinoid Receptor Agonists ; Cannabinoids ; Receptor, Cannabinoid, CB2
    Language English
    Publishing date 2015-01-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2014.11.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3203: Show issues Location:
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  4. Article: Calpain inhibitors and antioxidants act synergistically to prevent cell necrosis: effects of the novel dual inhibitors (cysteine protease inhibitor and antioxidant) BN 82204 and its pro-drug BN 82270.

    Pignol, Bernadette / Auvin, Serge / Carré, Denis / Marin, Jean-Grégoire / Chabrier, Pierre-Etienne

    Journal of neurochemistry

    2006  Volume 98, Issue 4, Page(s) 1217–1228

    Abstract: Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in ... ...

    Abstract Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in combination to protect cells against necrosis. Maitotoxin (MTX), which induces a massive influx of calcium, was used to provoke neuronal cell death. This toxin increased, in a concentration-dependent manner, both calpain activity and ROS formation. Calpain inhibitors or antioxidants inhibited MTX-induced necrosis only marginally (below 20%), whereas their association protected against cell death by 40-66% in a synergistic manner. BN 82204, which possesses both calpain-cathepsin L inhibitory and antioxidant properties, and its acetylated pro-drug BN 82270, totally protected cells at 100 microm. The pro-drug BN 82270, which had better cell penetration, was twice as effective as the active principle BN 82204 in protecting glioma C6 or neuroblastoma SHSY5Y cells against death. These results suggest the potential therapeutic relevance of using a single molecule with multiple activities (cysteine protease inhibitor/antioxidant), and warrant further in vivo investigations in models of neuronal disorders.
    MeSH term(s) Animals ; Antioxidants/pharmacology ; Calpain/antagonists & inhibitors ; Calpain/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cysteine Proteinase Inhibitors/pharmacology ; Dinoprost/analogs & derivatives ; Dinoprost/metabolism ; Drug Synergism ; Humans ; Lipid Peroxidation/drug effects ; Methotrexate/pharmacology ; Necrosis ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Phenothiazines/pharmacology ; Proteasome Endopeptidase Complex/metabolism ; Rats ; Rats, Sprague-Dawley ; Serine Endopeptidases/pharmacology
    Chemical Substances Antioxidants ; BN 82204 ; Cysteine Proteinase Inhibitors ; Nucleic Acid Synthesis Inhibitors ; Phenothiazines ; 8-epi-prostaglandin F2alpha (27415-26-5) ; Dinoprost (B7IN85G1HY) ; Serine Endopeptidases (EC 3.4.21.-) ; Calpain (EC 3.4.22.-) ; CAPN1 protein, human (EC 3.4.22.52) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Methotrexate (YL5FZ2Y5U1)
    Language English
    Publishing date 2006-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/j.1471-4159.2006.03952.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui II Zs.170: Show issues Location:
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  5. Article: Novel dual inhibitors of calpain and lipid peroxidation with enhanced cellular activity.

    Auvin, Serge / Pignol, Bernadette / Navet, Edith / Troadec, Morgane / Carré, Denis / Camara, José / Bigg, Dennis / Chabrier, Pierre-E

    Bioorganic & medicinal chemistry letters

    2006  Volume 16, Issue 6, Page(s) 1586–1589

    Abstract: A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic ... ...

    Abstract A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.
    MeSH term(s) Animals ; Antioxidants/chemical synthesis ; Antioxidants/pharmacology ; Brain/drug effects ; Calpain/antagonists & inhibitors ; Calpain/metabolism ; Cell Death/drug effects ; Dipeptides/chemical synthesis ; Dipeptides/pharmacology ; Glioma/drug therapy ; Humans ; Inhibitory Concentration 50 ; Lipid Peroxidation/drug effects ; Microsomes/drug effects ; Rats ; Structure-Activity Relationship
    Chemical Substances Antioxidants ; Dipeptides ; Calpain (EC 3.4.22.-)
    Language English
    Publishing date 2006-03-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2005.12.036
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Novel dual inhibitors of calpain and lipid peroxidation.

    Auvin, Serge / Pignol, Bernadette / Navet, Edith / Pons, Dominique / Marin, Jean-G / Bigg, Dennis / Chabrier, Pierre-E

    Bioorganic & medicinal chemistry letters

    2004  Volume 14, Issue 14, Page(s) 3825–3828

    Abstract: A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. ... ...

    Abstract A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. Compound 7, the most potent in cellular calpain and lipid peroxidation inhibitions, provided effective protection against glial cell death induced by maitotoxin.
    MeSH term(s) Antioxidants/chemical synthesis ; Antioxidants/pharmacology ; Calpain/antagonists & inhibitors ; Calpain/metabolism ; Cell Death/drug effects ; Furans/chemistry ; Humans ; Inhibitory Concentration 50 ; Leucine/chemistry ; Lipid Peroxidation/drug effects ; Lipoxygenase Inhibitors/chemical synthesis ; Lipoxygenase Inhibitors/pharmacology ; Neuroglia ; Structure-Activity Relationship
    Chemical Substances Antioxidants ; Furans ; Lipoxygenase Inhibitors ; Calpain (EC 3.4.22.-) ; Leucine (GMW67QNF9C)
    Language English
    Publishing date 2004-07-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2004.04.105
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Novel inhibitors of neuronal nitric oxide synthase with potent antioxidant properties.

    Auvin, Serge / Auguet, Michel / Navet, Edith / Harnett, Jeremiah J / Viossat, Isabelle / Schulz, Jocelyne / Bigg, Dennis / Chabrier, Pierre E

    Bioorganic & medicinal chemistry letters

    2003  Volume 13, Issue 2, Page(s) 209–212

    Abstract: A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid ... ...

    Abstract A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.
    MeSH term(s) Antioxidants/chemical synthesis ; Antioxidants/pharmacology ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/pharmacology ; Lipid Peroxidation/drug effects ; Lipoxygenase Inhibitors/chemical synthesis ; Lipoxygenase Inhibitors/pharmacology ; Nitric Oxide Synthase/antagonists & inhibitors ; Nitric Oxide Synthase Type I ; Nitric Oxide Synthase Type III ; Propofol/analogs & derivatives ; Propofol/chemical synthesis ; Propofol/pharmacology ; Substrate Specificity
    Chemical Substances Antioxidants ; Enzyme Inhibitors ; Lipoxygenase Inhibitors ; Nitric Oxide Synthase (EC 1.14.13.39) ; Nitric Oxide Synthase Type I (EC 1.14.13.39) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Propofol (YI7VU623SF)
    Language English
    Publishing date 2003-01-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/s0960-894x(02)00883-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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