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  1. Article ; Online: Design and optimization of selective and potent CDK9 inhibitors with flavonoid scaffold for the treatment of acute myeloid leukemia.

    Wu, Tizhi / Yu, Bin / Gong, Weihong / Zhang, Jing / Yu, Sixian / Tian, Yucheng / Zhao, Tengteng / Li, Zhiyu / Wang, Jubo / Bian, Jinlei

    European journal of medicinal chemistry

    2023  Volume 259, Page(s) 115711

    Abstract: Acute myeloid leukemia (AML) is a prevalent hematological tumor associated with a high morbidity and mortality rate. CDK9, functioning as a pivotal transcriptional regulator, facilitates transcriptional elongation through phosphorylation of RNA ... ...

    Abstract Acute myeloid leukemia (AML) is a prevalent hematological tumor associated with a high morbidity and mortality rate. CDK9, functioning as a pivotal transcriptional regulator, facilitates transcriptional elongation through phosphorylation of RNA polymerase II, which further governs the protein levels of Mcl-1 and c-Myc. Therefore, CDK9 has been considered as a promising therapeutic target for AML treatment. Here, we present the design, synthesis, and evaluation of CDK9 inhibitors bearing a flavonoid scaffold. Among them, compound 21a emerged as a highly selective CDK9 inhibitor (IC
    MeSH term(s) Humans ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Flavonoids/pharmacology ; Flavonoids/therapeutic use ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Leukemia, Myeloid, Acute/pathology ; Apoptosis ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Cell Line, Tumor ; Cyclin-Dependent Kinase 9/metabolism
    Chemical Substances Antineoplastic Agents ; Flavonoids ; Myeloid Cell Leukemia Sequence 1 Protein ; Protein Kinase Inhibitors ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22) ; CDK9 protein, human (EC 2.7.11.22)
    Language English
    Publishing date 2023-08-09
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2023.115711
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 784: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer.

    Wu, Tizhi / Yu, Bin / Xu, Yifan / Du, Zekun / Zhang, Zhiming / Wang, Yuxiao / Chen, Haoming / Zhang, Li Ao / Chen, Rui / Ma, Feihai / Gong, Weihong / Yu, Sixian / Qiu, Zhixia / Wu, Hongxi / Xu, Xi / Wang, Jubo / Li, Zhiyu / Bian, Jinlei

    Journal of medicinal chemistry

    2023  Volume 66, Issue 22, Page(s) 15340–15361

    Abstract: Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic ... ...

    Abstract Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcription, has emerged as a promising target for the development of antitumor drugs due to its crucial role in modulating the levels of antiapoptotic protein Mcl-1. Herein, we present the synthesis, optimization, and evaluation of selective CDK9 inhibitors with a macrocyclic scaffold that effectively suppresses the growth of NSCLC cells. Notably, compound
    MeSH term(s) Humans ; Aniline Compounds/pharmacology ; Aniline Compounds/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Cell Line, Tumor ; Cyclin-Dependent Kinase 9 ; Drug Resistance, Neoplasm ; ErbB Receptors/metabolism ; Lung Neoplasms/drug therapy ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Macrocyclic Compounds/pharmacology ; Macrocyclic Compounds/therapeutic use
    Chemical Substances Aniline Compounds ; CDK9 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22) ; ErbB Receptors (EC 2.7.10.1) ; osimertinib (3C06JJ0Z2O) ; Protein Kinase Inhibitors ; Macrocyclic Compounds
    Language English
    Publishing date 2023-10-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c01400
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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  3. Article ; Online: Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy.

    Wu, Tizhi / Zhang, Zhiming / Gong, Guangyue / Du, Zekun / Xu, Yifan / Yu, Sixian / Ma, Feihai / Zhang, Xuan / Wang, Yuxiao / Chen, Haoming / Wu, Shiqi / Xu, Xi / Qiu, Zhixia / Li, Zhiyu / Wu, Hongxi / Bian, Jinlei / Wang, Jubo

    European journal of medicinal chemistry

    2023  Volume 260, Page(s) 115774

    Abstract: CDK9 plays a vital role in regulating RNA transcription and significantly impacts the expression of short-lived proteins such as Mcl-1 and c-Myc. Thus, targeting CDK9 holds great promise for the development of antitumor drugs. Natural flavonoid ... ...

    Abstract CDK9 plays a vital role in regulating RNA transcription and significantly impacts the expression of short-lived proteins such as Mcl-1 and c-Myc. Thus, targeting CDK9 holds great promise for the development of antitumor drugs. Natural flavonoid derivatives have recently gained considerable attention in the field of antitumor drug research due to their broad bioactivity and low toxicity. In this study, the PROTAC strategy was used to perform structural modifications of the flavonoid derivative LWT-111 to design a series of flavonoid-based CDK9 degraders. Notably, compound CP-07 emerged as a potent CDK9 degrader, effectively suppressing the proliferation and colony formation of 22RV1 cells by downregulating Mcl-1 and c-Myc. Moreover, CP-07 exhibited significant tumor growth inhibition with a TGI of 75.1% when administered at a dose of 20 mg/kg in the 22RV1 xenograft tumor model. These findings demonstrated the potential of CP-07 as a powerful flavonoid-based CDK9 degrader for prostate cancer therapy.
    MeSH term(s) Male ; Animals ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein ; Prostatic Neoplasms/drug therapy ; Disease Models, Animal ; Flavonoids/pharmacology ; Heterografts ; Cyclin-Dependent Kinase 9
    Chemical Substances Myeloid Cell Leukemia Sequence 1 Protein ; Flavonoids ; CDK9 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22)
    Language English
    Publishing date 2023-09-01
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2023.115774
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.B 784: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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