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  1. Article ; Online: N-terminal selective conjugation method widens the therapeutic window of antibody-drug conjugates by improving tolerability and stability.

    Ko, Min Ji / Song, Daehae / Kim, Juhee / Kim, Jae Yong / Eom, Jaehyun / Sung, Byungje / Son, Yong-Gyu / Kim, Young Min / Lee, Sang Hoon / You, Weon-Kyoo / Jung, Jinwon

    mAbs

    2021  Volume 13, Issue 1, Page(s) 1914885

    Abstract: Antibody-drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and ...

    Abstract Antibody-drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and narrow therapeutic windows. To overcome these limitations, we have applied reductive alkylation to develop a new type of ADC that has cytotoxic drugs conjugated to the N-terminal of an antibody through amine bonds introduced via reductive alkylation reactions (NTERM). To test whether the NTERM-conjugated ADCs can widen therapeutic windows, we synthesized three different ADCs by conjugating trastuzumab and monomethyl auristatin-F using three different methods, and compared their stability, efficacy, and toxicity. The NTERM-conjugated ADC was more stable
    MeSH term(s) Alkylation ; Animals ; Antineoplastic Agents, Immunological/chemistry ; Antineoplastic Agents, Immunological/pharmacokinetics ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Agents, Immunological/toxicity ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Drug Compounding ; Drug Stability ; Female ; Immunoconjugates/chemistry ; Immunoconjugates/pharmacokinetics ; Immunoconjugates/pharmacology ; Immunoconjugates/toxicity ; Oligopeptides/chemistry ; Oligopeptides/pharmacokinetics ; Oligopeptides/pharmacology ; Oligopeptides/toxicity ; Protein Stability ; Rats, Nude ; Rats, Sprague-Dawley ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; Trastuzumab/chemistry ; Trastuzumab/pharmacokinetics ; Trastuzumab/pharmacology ; Trastuzumab/toxicity ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; Rats
    Chemical Substances Antineoplastic Agents, Immunological ; Immunoconjugates ; Oligopeptides ; monomethylauristatin F ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
    Language English
    Publishing date 2021-04-27
    Publishing country United States
    Document type Comparative Study ; Journal Article
    ZDB-ID 2537838-7
    ISSN 1942-0870 ; 1942-0870
    ISSN (online) 1942-0870
    ISSN 1942-0870
    DOI 10.1080/19420862.2021.1914885
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: ABL001, a Bispecific Antibody Targeting VEGF and DLL4, with Chemotherapy, Synergistically Inhibits Tumor Progression in Xenograft Models.

    Yeom, Dong-Hoon / Lee, Yo-Seob / Ryu, Ilhwan / Lee, Sunju / Sung, Byungje / Lee, Han-Byul / Kim, Dongin / Ahn, Jin-Hyung / Ha, Eunsin / Choi, Yong-Soo / Lee, Sang Hoon / You, Weon-Kyoo

    International journal of molecular sciences

    2020  Volume 22, Issue 1

    Abstract: Delta-like-ligand 4 (DLL4) is a promising target to augment the effects of VEGF inhibitors. A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in ... ...

    Abstract Delta-like-ligand 4 (DLL4) is a promising target to augment the effects of VEGF inhibitors. A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in xenograft models. A bispecific antibody targeting VEGF and DLL4 (ABL001/NOV1501/TR009) demonstrates more potent in vitro and in vivo biological activity compared to VEGF or DLL4 targeting monoclonal antibodies alone and is currently being evaluated in a phase 1 clinical study of heavy chemotherapy or targeted therapy pre-treated cancer patients (ClinicalTrials.gov Identifier: NCT03292783). However, the effects of a combination of ABL001 and chemotherapy on tumor vessels and tumors are not known. Hence, the effects of ABL001, with or without paclitaxel and irinotecan were evaluated in human gastric or colon cancer xenograft models. The combination treatment synergistically inhibited tumor progression compared to each monotherapy. More tumor vessel regression and apoptotic tumor cell induction were observed in tumors treated with the combination therapy, which might be due to tumor vessel normalization. Overall, these findings suggest that the combination therapy of ABL001 with paclitaxel or irinotecan would be a better clinical strategy for the treatment of cancer patients.
    MeSH term(s) Adaptor Proteins, Signal Transducing/antagonists & inhibitors ; Animals ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; Apoptosis/drug effects ; Calcium-Binding Proteins/antagonists & inhibitors ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Drug Synergism ; Humans ; Mice ; Neovascularization, Pathologic/drug therapy ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Niacinamide/therapeutic use ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Xenograft Model Antitumor Assays
    Chemical Substances Adaptor Proteins, Signal Transducing ; Antibodies, Bispecific ; Calcium-Binding Proteins ; DLL4 protein, human ; Pyrazoles ; Vascular Endothelial Growth Factor A ; asciminib ; Niacinamide (25X51I8RD4)
    Language English
    Publishing date 2020-12-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22010241
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier.

    Shin, Jung-Won / An, Sungwon / Kim, Dongin / Kim, Hyunjoo / Ahn, Jinhyung / Eom, Jaehyun / You, Weon-Kyoo / Yun, Hyesu / Lee, Bora / Sung, Byungje / Jung, Jinwon / Kim, Sehyun / Son, Yonggyu / Sung, Eunsil / Lee, Hanbyul / Lee, Suyeon / Song, Daehae / Pak, Youngdon / Sandhu, Jagdeep K /
    Haqqani, Arsalan S / Stanimirovic, Danica B / Yoo, Jiseon / Kim, Donghwan / Maeng, Sungho / Lee, Jeonghun / Lee, Sang Hoon

    Cell reports methods

    2022  Volume 2, Issue 11, Page(s) 100338

    Abstract: Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular ... ...

    Abstract Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular shuttles. However, the TfR-based approach raises concerns about safety and developmental burden. Here, we report insulin-like growth factor 1 receptor (IGF1R) as an ideal target for the molecular shuttle. We also describe Grabody B, an antibody against IGF1R, as a molecular shuttle. Grabody B has broad cross-species reactivity and does not interfere with IGF1R-mediated signaling. We demonstrate that administration of Grabody B-fused anti-alpha-synuclein (α-Syn) antibody induces better improvement in neuropathology and behavior in a Parkinson's disease animal model than the therapeutic antibody alone due to its superior serum pharmacokinetics and enhanced brain exposure. The results indicate that IGF1R is an ideal shuttle target and Grabody B is a safe and efficient molecular shuttle.
    MeSH term(s) Animals ; Blood-Brain Barrier/metabolism ; Biological Products/metabolism ; Endothelial Cells/metabolism ; Brain/metabolism ; Biological Transport ; Antibodies/metabolism
    Chemical Substances Biological Products ; Antibodies
    Language English
    Publishing date 2022-11-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2667-2375
    ISSN (online) 2667-2375
    DOI 10.1016/j.crmeth.2022.100338
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125.

    Heo, Yong-Seok / Kim, Su-Kyoung / Seo, Chang Il / Kim, Young Kwan / Sung, Byung-Je / Lee, Hye Shin / Lee, Jae Il / Park, Sam-Yong / Kim, Jin Hwan / Hwang, Kwang Yeon / Hyun, Young-Lan / Jeon, Young Ho / Ro, Seonggu / Cho, Joong Myung / Lee, Tae Gyu / Yang, Chul-Hak

    The EMBO journal

    2004  Volume 23, Issue 11, Page(s) 2185–2195

    Abstract: The c-jun N-terminal kinase (JNK) signaling pathway is regulated by JNK-interacting protein-1 (JIP1), which is a scaffolding protein assembling the components of the JNK cascade. Overexpression of JIP1 deactivates the JNK pathway selectively by ... ...

    Abstract The c-jun N-terminal kinase (JNK) signaling pathway is regulated by JNK-interacting protein-1 (JIP1), which is a scaffolding protein assembling the components of the JNK cascade. Overexpression of JIP1 deactivates the JNK pathway selectively by cytoplasmic retention of JNK and thereby inhibits gene expression mediated by JNK, which occurs in the nucleus. Here, we report the crystal structure of human JNK1 complexed with pepJIP1, the peptide fragment of JIP1, revealing its selectivity for JNK1 over other MAPKs and the allosteric inhibition mechanism. The van der Waals contacts by the three residues (Pro157, Leu160, and Leu162) of pepJIP1 and the hydrogen bonding between Glu329 of JNK1 and Arg156 of pepJIP1 are critical for the selective binding. Binding of the peptide also induces a hinge motion between the N- and C-terminal domains of JNK1 and distorts the ATP-binding cleft, reducing the affinity of the kinase for ATP. In addition, we also determined the ternary complex structure of pepJIP1-bound JNK1 complexed with SP600125, an ATP-competitive inhibitor of JNK, providing the basis for the JNK specificity of the compound.
    MeSH term(s) Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/metabolism ; Adenosine Triphosphate/metabolism ; Allosteric Regulation ; Anthracenes/metabolism ; Arginine/chemistry ; Binding Sites ; Blotting, Western ; Calorimetry ; Crystallography, X-Ray ; Glutamic Acid/chemistry ; HeLa Cells ; Humans ; Hydrogen Bonding ; Leucine/chemistry ; Mitogen-Activated Protein Kinase 8/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 8/chemistry ; Models, Molecular ; Proline/chemistry ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Signal Transduction ; Transfection
    Chemical Substances Adaptor Proteins, Signal Transducing ; Anthracenes ; MAPK8IP1 protein, human ; pyrazolanthrone (1TW30Y2766) ; Glutamic Acid (3KX376GY7L) ; Adenosine Triphosphate (8L70Q75FXE) ; Arginine (94ZLA3W45F) ; Proline (9DLQ4CIU6V) ; Mitogen-Activated Protein Kinase 8 (EC 2.7.11.24) ; Leucine (GMW67QNF9C)
    Language English
    Publishing date 2004-06-02
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.1038/sj.emboj.7600212
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1808: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  5. Article ; Online: Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.

    Sung, Byung-Je / Hwang, Kwang Yeon / Jeon, Young Ho / Lee, J I / Heo, Yong-Seok / Kim, Jin Hwan / Moon, Jinho / Yoon, Jung Min / Hyun, Young-Lan / Kim, Eunmi / Eum, Sung Jin / Park, Sam-Yong / Lee, Jie-Oh / Lee, Tae Gyu / Ro, Seonggu / Cho, Joong Myung

    Nature

    2003  Volume 425, Issue 6953, Page(s) 98–102

    Abstract: Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the ...

    Abstract Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.
    MeSH term(s) 3',5'-Cyclic-GMP Phosphodiesterases ; Binding Sites ; Carbolines/chemistry ; Carbolines/metabolism ; Catalytic Domain ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Humans ; Hydrogen Bonding ; Imidazoles/chemistry ; Imidazoles/metabolism ; Models, Molecular ; Phosphoric Diester Hydrolases/chemistry ; Phosphoric Diester Hydrolases/metabolism ; Piperazines/chemistry ; Piperazines/metabolism ; Protein Conformation ; Purines ; Sildenafil Citrate ; Sulfones ; Tadalafil ; Triazines ; Vardenafil Dihydrochloride
    Chemical Substances Carbolines ; Imidazoles ; Piperazines ; Purines ; Sulfones ; Triazines ; Vardenafil Dihydrochloride (5O8R96XMH7) ; Tadalafil (742SXX0ICT) ; Sildenafil Citrate (BW9B0ZE037) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; 3',5'-Cyclic-GMP Phosphodiesterases (EC 3.1.4.35) ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; PDE5A protein, human (EC 3.1.4.35)
    Language English
    Publishing date 2003-09-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature01914
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

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