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  1. Article ; Online: ITK degradation to block T cell receptor signaling and overcome therapeutic resistance in T cell lymphomas.

    Jiang, Baishan / Weinstock, David M / Donovan, Katherine A / Sun, Hong-Wei / Wolfe, Ashley / Amaka, Sam / Donaldson, Nicholas L / Wu, Gongwei / Jiang, Yuan / Wilcox, Ryan A / Fischer, Eric S / Gray, Nathanael S / Wu, Wenchao

    Cell chemical biology

    2023  Volume 30, Issue 4, Page(s) 383–393.e6

    Abstract: Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug ... ...

    Abstract Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug Administration (FDA) approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.
    MeSH term(s) Humans ; Signal Transduction ; Receptors, Antigen, T-Cell/metabolism ; Drug Resistance, Neoplasm ; T-Lymphocytes ; Lymphoma, T-Cell/drug therapy
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-04-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2023.03.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1.

    Wu, Wenchao / Nelson, Geoffrey M / Koch, Raphael / Donovan, Katherine A / Nowak, Radosław P / Heavican-Foral, Tayla B / Nirmal, Ajit J / Liu, Huiyun / Yang, Lei / Duffy, Jessica / Powers, Foster / Stevenson, Kristen E / Jones, Marcus Kenneth / Ng, Samuel Y / Wu, Gongwei / Jain, Salvia / Xu, Ran / Amaka, Sam / Trevisani, Christopher /
    Donaldson, Nicholas L / Hagner, Patrick R / de Leval, Laurence / Gaulard, Philippe / Iqbal, Javeed / Thakurta, Anjan / Fischer, Eric S / Adelman, Karen / Weinstock, David M

    Blood

    2021  Volume 139, Issue 13, Page(s) 2024–2037

    Abstract: Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas ...

    Abstract Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2-mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.
    MeSH term(s) Drug Resistance, Neoplasm ; Humans ; Ikaros Transcription Factor/metabolism ; Immunologic Factors/pharmacology ; Lenalidomide/pharmacology ; Lymphoma, T-Cell/drug therapy ; Multiple Myeloma/drug therapy ; Thalidomide/analogs & derivatives ; Thalidomide/pharmacology ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
    Chemical Substances IKZF1 protein, human ; Immunologic Factors ; Ikaros Transcription Factor (148971-36-2) ; Thalidomide (4Z8R6ORS6L) ; pomalidomide (D2UX06XLB5) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; ZFP91 protein, human (EC 6.3.2.-) ; Lenalidomide (F0P408N6V4)
    Language English
    Publishing date 2021-12-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2021014701
    Database MEDical Literature Analysis and Retrieval System OnLINE

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