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  1. Article ; Online: Correction to: Ionizing radiation-induced NF-κB activation requires PARP-1 function to confer radioresistance.

    Veuger, Stephany J / Hunter, Jill E / Durkacz, Barbara W

    Oncogene

    2023  Volume 42, Issue 7, Page(s) 546–547

    Language English
    Publishing date 2023-01-26
    Publishing country England
    Document type Published Erratum
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-023-02605-w
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  2. Article ; Online: Increased migration and motility in XIAP-null cells mediated by the C-RAF protein kinase.

    Russell, Lauren G / Davis, Lydia A K / Hunter, Jill E / Perkins, Neil D / Kenneth, Niall S

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 7943

    Abstract: The product encoded by the X-linked inhibitor of apoptosis (XIAP) gene is a multi-functional protein which not only controls caspase-dependent cell death, but also participates in inflammatory signalling, copper homeostasis, response to hypoxia and ... ...

    Abstract The product encoded by the X-linked inhibitor of apoptosis (XIAP) gene is a multi-functional protein which not only controls caspase-dependent cell death, but also participates in inflammatory signalling, copper homeostasis, response to hypoxia and control of cell migration. Deregulation of XIAP, either by elevated expression or inherited genetic deletion, is associated with several human disease states. Reconciling XIAP-dependent signalling pathways with its role in disease progression is essential to understand how XIAP promotes the progression of human pathologies. In this study we have created a panel of genetically modified XIAP-null cell lines using TALENs and CRISPR/Cas9 to investigate the functional outcome of XIAP deletion. Surprisingly, in our genetically modified cells XIAP deletion had no effect on programmed cell death, but instead the primary phenotype we observed was a profound increase in cell migration rates. Furthermore, we found that XIAP-dependent suppression of cell migration was dependent on XIAPdependent control of C-RAF levels, a protein kinase which controls cell signalling pathways that regulate the cytoskeleton. These results suggest that XIAP is not necessary for control of the apoptotic signalling cascade, however it does have a critical role in controlling cell migration and motility that cannot be compensated for in XIAP-knockout cells.
    MeSH term(s) Apoptosis ; Caspases/metabolism ; Lymphocytes, Null/metabolism ; Proto-Oncogene Proteins c-raf/metabolism ; Signal Transduction ; X-Linked Inhibitor of Apoptosis Protein/metabolism
    Chemical Substances X-Linked Inhibitor of Apoptosis Protein ; Proto-Oncogene Proteins c-raf (EC 2.7.11.1) ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2022-05-13
    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/s41598-022-11438-8
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  3. Article: Expression and Activity of the NF-κB Subunits in Chronic Lymphocytic Leukaemia: A Role for RelB and Non-Canonical Signalling.

    Mulligan, Evan A / Tudhope, Susan J / Hunter, Jill E / Clift, Arabella E G / Elliott, Sarah L / Summerfield, Geoffrey P / Wallis, Jonathan / Pepper, Chris J / Durkacz, Barabara / Veuger, Stephany / Willmore, Elaine

    Cancers

    2023  Volume 15, Issue 19

    Abstract: Background: Canonical NF-κB signalling by p65 (RelA) confers chemo-resistance and poor survival in chronic lymphocytic leukaemia (CLL). The role of non-canonical NF-κB signalling (leading to RelB and p52 subunit activation) in CLL is less understood, ... ...

    Abstract Background: Canonical NF-κB signalling by p65 (RelA) confers chemo-resistance and poor survival in chronic lymphocytic leukaemia (CLL). The role of non-canonical NF-κB signalling (leading to RelB and p52 subunit activation) in CLL is less understood, but given its importance in other B-cell tumour types, we theorised that RelB and p52 may also contribute to the pathology of CLL.
    Methods: DNA binding activity of all five NF-kB subunits, p65, p50, RelB, p52, and c-Rel, was quantified using ELISA and correlated to ex vivo chemoresistance, CD40L-stimulated signalling (to mimic the lymph node microenvironment), and clinical data.
    Results: Importantly, we show for the first time that high basal levels of RelB DNA binding correlate with nuclear RelB protein expression and are associated with del(11q), ATM dysfunction, unmutated IGHV genes, and shorter survival. High levels of nuclear p65 are prevalent in del(17p) cases (including treatment-naïve patients) and also correlate with the outcome. CD40L-stimulation resulted in rapid RelB activation, phosphorylation and processing of p100, and subsequent CLL cell proliferation.
    Conclusions: These data highlight a role for RelB in driving CLL cell tumour growth in a subset of patients and therefore strategies designed to inhibit non-canonical NF-κB signalling represent a novel approach that will have therapeutic benefit in CLL.
    Language English
    Publishing date 2023-09-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers15194736
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  4. Article ; Online: c-Rel and its many roles in cancer: an old story with new twists.

    Hunter, Jill E / Leslie, Jack / Perkins, Neil D

    British journal of cancer

    2016  Volume 114, Issue 1, Page(s) 1–6

    Abstract: When the genes encoding NF-κB subunits were first isolated, their homology to the previously identified c-Rel proto-oncogene and its viral homologue v-Rel was clear. This provided the first indication that these transcription factors also had a role in ... ...

    Abstract When the genes encoding NF-κB subunits were first isolated, their homology to the previously identified c-Rel proto-oncogene and its viral homologue v-Rel was clear. This provided the first indication that these transcription factors also had a role in cancer. Because of its homology to v-Rel, which transforms chicken B cells together with the important role c-Rel can have as a regulator of B- and T-cell proliferation, most attention has focussed on its role in B-cell lymphomas, where the REL gene is frequently amplified. However, a growing number of reports now indicate that c-Rel has important functions in many solid tumours, although studies in mice suggest it may not always function as an oncogene. Moreover, c-Rel is a critical regulator of fibrosis, which provides an environment for tumour development in many settings. Overall, c-Rel is emerging as a complex regulator of tumorigenesis, and there is still much to learn about its functions in human malignancies and the response to cancer therapies.
    MeSH term(s) Animals ; Fibrosis ; Genes, p53/physiology ; Genes, rel/physiology ; Humans ; Lymphoma, B-Cell/etiology ; Mice ; Neoplasms/etiology ; Neoplasms/therapy ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-rel/chemistry ; Proto-Oncogene Proteins c-rel/physiology
    Chemical Substances MAS1 protein, human ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-rel
    Language English
    Publishing date 2016-01-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/bjc.2015.410
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  5. Article ; Online: c-Rel-dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis.

    Leslie, Jack / Hunter, Jill E / Collins, Amy / Rushton, Amelia / Russell, Lauren G / Ramon-Gil, Erik / Laszczewska, Maja / McCain, Misti / Zaki, Marco Y W / Knox, Amber / Seow, Yixin / Sabater, Laura / Geh, Daniel / Perkins, Neil D / Reeves, Helen L / Tiniakos, Dina / Mann, Derek A / Oakley, Fiona

    Hepatology (Baltimore, Md.)

    2023  Volume 78, Issue 4, Page(s) 1050–1063

    Abstract: Background and aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we ... ...

    Abstract Background and aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c-Rel in HCC.
    Approach and results: Histological and transcriptional studies confirmed expression of c-Rel in human patients with HCC, but low c-Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo , global ( Rel-/- ) and epithelial specific ( RelAlb ) c-Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild-type (WT) controls 30 weeks after N-diethylnitrosamine injury. However, tumor burden was comparable when c-Rel was deleted in hepatocytes once tumors were established, suggesting c-Rel signaling is important for preventing HCC initiation after genotoxic injury, rather than for HCC progression. In vitro , Rel-/- hepatocytes were more susceptible to genotoxic injury than WT controls. ATM-CHK2 DNA damage response pathway proteins were suppressed in Rel-/- hepatocytes following genotoxic injury, suggesting that c-Rel is required for effective DNA repair. To determine if c-Rel inhibition sensitizes cancer cells to chemotherapy, by preventing repair of chemotherapy-induced DNA damage, thus increasing tumor cell death, we administered single or combination doxorubicin and IT-603 (c-Rel inhibitor) therapy in an orthotopic HCC model. Indeed, combination therapy was more efficacious than doxorubicin alone.
    Conclusion: Hepatocyte c-Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c-Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.
    MeSH term(s) Animals ; Humans ; Mice ; Carcinogenesis/genetics ; Carcinoma, Hepatocellular/pathology ; DNA Damage ; Doxorubicin/pharmacology ; Hepatocytes/metabolism ; Liver Neoplasms/metabolism ; Mice, Knockout ; NF-kappa B/metabolism ; Proto-Oncogene Proteins c-rel/metabolism
    Chemical Substances Doxorubicin (80168379AG) ; NF-kappa B ; Proto-Oncogene Proteins c-rel
    Language English
    Publishing date 2023-09-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604603-4
    ISSN 1527-3350 ; 0270-9139
    ISSN (online) 1527-3350
    ISSN 0270-9139
    DOI 10.1002/hep.32781
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  6. Article ; Online: Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Eµ-Myc lymphoma cells.

    Hunter, Jill E / Campbell, Amy E / Kerridge, Scott / Fraser, Callum / Hannaway, Nicola L / Luli, Saimir / Ivanova, Iglika / Brownridge, Philip J / Coxhead, Jonathan / Taylor, Leigh / Leary, Peter / Hasoon, Megan S R / Eyers, Claire E / Perkins, Neil D

    The Biochemical journal

    2022  Volume 479, Issue 19, Page(s) 2131–2151

    Abstract: The development of resistance and the activation of bypass pathway signalling represents a major problem for the clinical application of protein kinase inhibitors. While investigating the effect of either a c-Rel deletion or RelAT505A phosphosite knockin ...

    Abstract The development of resistance and the activation of bypass pathway signalling represents a major problem for the clinical application of protein kinase inhibitors. While investigating the effect of either a c-Rel deletion or RelAT505A phosphosite knockin on the Eµ-Myc mouse model of B-cell lymphoma, we discovered that both NF-κB subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since Eµ-Myc lymphomas depend on CHK1 activity to cope with high levels of DNA replication stress and consequent genomic instability, it was not clear how these mutant NF-κB subunit lymphomas were able to survive. To understand these survival mechanisms and to identify potential compensatory bypass signalling pathways in these lymphomas, we applied a multi-omics strategy. With c-Rel-/- Eµ-Myc lymphomas we observed high levels of Phosphatidyl-inositol 3-kinase (PI3K) and AKT pathway activation. Moreover, treatment with the PI3K inhibitor Pictilisib (GDC-0941) selectively inhibited the growth of reimplanted c-Rel-/- and RelAT505A, but not wild type (WT) Eµ-Myc lymphomas. We also observed up-regulation of a RHO/RAC pathway gene expression signature in both Eµ-Myc NF-κB subunit mutation models. Further investigation demonstrated activation of the RHO/RAC effector p21-activated kinase (PAK) 2. Here, the PAK inhibitor, PF-3758309 successfully overcame resistance of RelAT505A but not WT lymphomas. These findings demonstrate that up-regulation of multiple bypass pathways occurs in CHK1 inhibitor resistant Eµ-Myc lymphomas. Consequently, drugs targeting these pathways could potentially be used as either second line or combinatorial therapies to aid the successful clinical application of CHK1 inhibitors.
    MeSH term(s) Animals ; Inositol ; Lymphoma/drug therapy ; Lymphoma/genetics ; Lymphoma/metabolism ; Mice ; Mice, Transgenic ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinase/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Up-Regulation ; p21-Activated Kinases/genetics
    Chemical Substances NF-kappa B ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-myc ; Inositol (4L6452S749) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2022-10-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220103
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  7. Article ; Online: Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential.

    Madgwick, Suzanne / Luli, Saimir / Sellier, Helene / Butterworth, Jacqueline A / Leslie, Jack / Moore, Adam J / Corbin, Emma K / Yemm, Adrian I / Chiremba, Robson T / Tiniakos, Dina / Oakley, Fiona / Perkins, Neil D / Hunter, Jill E

    The Biochemical journal

    2022  Volume 479, Issue 19, Page(s) 2115–2130

    Abstract: Claspin is an adaptor protein required for ATR-dependent phosphorylation of CHK1 during S-phase following DNA replication stress. Claspin expression is highly variable in cancer, with low levels frequently correlating with poor patient survival. To learn ...

    Abstract Claspin is an adaptor protein required for ATR-dependent phosphorylation of CHK1 during S-phase following DNA replication stress. Claspin expression is highly variable in cancer, with low levels frequently correlating with poor patient survival. To learn more about the biological consequences of reduced Claspin expression and its effects on tumorigenesis, we investigated mice with a heterozygous knockout of the Clspn gene. Claspin haploinsufficiency resulted in reduced female fertility and a maternally inherited defect in oocyte meiosis I cell cycle progression. Furthermore, aged Clspn+/- mice developed spontaneous lymphoid hyperplasia and increased susceptibility to non-alcoholic fatty liver disease. Importantly, we demonstrate a tumour suppressor role for Claspin. Reduced Claspin levels result in increased liver damage and tumourigenesis in the DEN model of hepatocellular carcinoma. These data reveal that Clspn haploinsufficiency has widespread unanticipated biological effects and establishes the importance of Claspin as a regulatory node controlling tumorigenesis and multiple disease aetiologies.
    MeSH term(s) Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Carcinogenesis/genetics ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Checkpoint Kinase 1 ; DNA Replication ; Female ; Fertility/genetics ; Haploinsufficiency ; Hyperplasia ; Mice ; Phosphorylation
    Chemical Substances Cell Cycle Proteins ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1)
    Language English
    Publishing date 2022-10-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220101
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  8. Article ; Online: Centrosome dysfunction associated with somatic expression of the synaptonemal complex protein TEX12.

    Sandhu, Sumit / Sou, Ieng F / Hunter, Jill E / Salmon, Lucy / Wilson, Caroline L / Perkins, Neil D / Hunter, Neil / Davies, Owen R / McClurg, Urszula L

    Communications biology

    2021  Volume 4, Issue 1, Page(s) 1371

    Abstract: The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein ... ...

    Abstract The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers.
    MeSH term(s) Animals ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Centrosome/physiology ; Gene Expression ; Humans ; Mice ; Synaptonemal Complex/metabolism
    Chemical Substances Cell Cycle Proteins ; TEX12 protein, human
    Language English
    Publishing date 2021-12-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-021-02887-4
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  9. Article ; Online: Mutation of the RelA(p65) Thr505 phosphosite disrupts the DNA replication stress response leading to CHK1 inhibitor resistance.

    Hunter, Jill E / Campbell, Amy E / Butterworth, Jacqueline A / Sellier, Helene / Hannaway, Nicola L / Luli, Saimir / Floudas, Achilleas / Kenneth, Niall S / Moore, Adam J / Brownridge, Philip J / Thomas, Huw D / Coxhead, Jonathan / Taylor, Leigh / Leary, Peter / Hasoon, Megan S R / Knight, Andrew M / Garrett, Michelle D / Collins, Ian / Eyers, Claire E /
    Perkins, Neil D

    The Biochemical journal

    2022  Volume 479, Issue 19, Page(s) 2087–2113

    MeSH term(s) DNA Replication ; Mutation ; Protein Kinase Inhibitors/pharmacology
    Chemical Substances Protein Kinase Inhibitors
    Language English
    Publishing date 2022-10-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220089
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  10. Article ; Online: Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway.

    Hunter, Jill E / Campbell, Amy E / Hannaway, Nicola L / Kerridge, Scott / Luli, Saimir / Butterworth, Jacqueline A / Sellier, Helene / Mukherjee, Reshmi / Dhillon, Nikita / Sudhindar, Praveen D / Shukla, Ruchi / Brownridge, Philip J / Bell, Hayden L / Coxhead, Jonathan / Taylor, Leigh / Leary, Peter / Hasoon, Megan S R / Collins, Ian / Garrett, Michelle D /
    Eyers, Claire E / Perkins, Neil D

    The Biochemical journal

    2022  Volume 479, Issue 19, Page(s) 2063–2086

    Abstract: Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel- ...

    Abstract Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel-/- cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel-/- lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of Eµ-Myc/cRel-/- lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT Eµ-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.
    MeSH term(s) Aminopyridines ; Animals ; Deubiquitinating Enzymes ; Lymphoma/metabolism ; Lymphoma/pathology ; Mice ; NF-kappa B/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proteomics ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Pyrimidines
    Chemical Substances 3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile ; Aminopyridines ; NF-kappa B ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-myc ; Pyrimidines ; Deubiquitinating Enzymes (EC 3.4.19.12)
    Language English
    Publishing date 2022-10-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220102
    Database MEDical Literature Analysis and Retrieval System OnLINE

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