Image_1_A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation.TIFF
T cell activation is mediated by signaling pathways originating from the T cell receptor (TCR). Propagation of signals downstream of the TCR involves a cascade of numerous kinases, some of which have yet to be identified. Through a screening strategy that we have previously introduced, PHA-767491, an inhibitor of the kinases Cdc7 and Cdk9, was identified to impede TCR signaling. PHA-767491 suppressed several T cell activation phenomena, including the expression of activation markers, proliferation, and effector functions. We also observed a defect in TCR signaling pathways upon PHA-767491 treatment. Inhibition of Cdc7/Cdk9 impairs T cell responses, which could potentially be detrimental for the immune response to tumors, and also compromises the ability to resist infections. The Cdc7/Cdk9 inhibitor is a strong candidate as a cancer therapeutic, but its effect on the immune system poses a problem for clinical applications.
History
References
- https://doi.org//10.1002/1439-7633(20020703)3:7<596::AID-CBIC596>3.0.CO;2-U
- https://doi.org//10.1016/j.bmcl.2015.05.100
- https://doi.org//10.1016/j.pharmthera.2017.02.008
- https://doi.org//10.1158/0008-5472.CAN-17-2782
- https://doi.org//10.1016/j.tips.2016.06.006
- https://doi.org//10.1016/j.tranon.2015.03.010
- https://doi.org//10.3389/fonc.2015.00278
- https://doi.org//10.1093/emboj/18.20.5703
- https://doi.org//10.1101/gad.13.16.2159
- https://doi.org//10.1128/MCB.13.5.2899
- https://doi.org//10.1101/gad.11.24.3365
- https://doi.org//10.1093/emboj/21.9.2168
- https://doi.org//10.1186/s13000-015-0360-7
- https://doi.org//10.1016/j.canlet.2013.05.008
- https://doi.org//10.1593/neo.08216
- https://doi.org//10.1016/j.humpath.2009.08.008
- https://doi.org//10.1158/0008-5472.CAN-04-1547
- https://doi.org//10.1038/nchembio.90
- https://doi.org//10.1016/j.bmcl.2012.04.024
- https://doi.org//10.7554/eLife.29736
- https://doi.org//10.1021/jm800977q
- https://doi.org//10.1016/j.cell.2018.09.051
- https://doi.org//10.1080/15384101.2016.1138186
- https://doi.org//10.1038/s41598-018-28106-5
- https://doi.org//10.3791/58946
- https://doi.org//10.1093/annonc/mdh947
- https://doi.org//10.1074/jbc.M110.201236
- https://doi.org//10.1371/journal.pone.0043191
- https://doi.org//10.1101/gad.12.4.480
- https://doi.org//10.1200/JCO.2005.03.7689
- https://doi.org//10.1046/j.1432-1033.2003.03794.x
- https://doi.org//10.1158/1535-7163.MCT-10-1119
- https://doi.org//10.1371/journal.pone.0113300
- https://doi.org//10.1074/jbc.M512921200
- https://doi.org//10.1111/bph.12408
- https://doi.org//10.1073/pnas.94.26.14320
- https://doi.org//10.1084/jem.20122528
- https://doi.org//10.1016/j.immuni.2005.09.012
- https://doi.org//10.1016/S0065-2776(07)96002-2
- https://doi.org//10.1038/nri3403
- https://doi.org//10.1021/jm0102046
- https://doi.org//10.1021/jm101346r
- https://doi.org//10.1242/jcs.03145
- https://doi.org//10.1002/ijc.10738
- https://doi.org//10.1021/jm0605740
- https://doi.org//10.1007/s00280-008-0921-5
- https://doi.org//10.1038/nri1632
- https://doi.org//10.1016/j.it.2013.02.002
- https://doi.org//10.1021/acschembio.7b00117
- https://doi.org//10.1084/jem.188.2.247
- https://doi.org//10.1084/jem.190.12.1879
- https://doi.org//10.1371/journal.pone.0068425
- https://doi.org//10.1126/scisignal.2000482
- https://doi.org//10.1101/gad.1933010
- https://doi.org//10.1034/j.1600-065X.2002.18609.x
- https://doi.org//10.1038/ncomms11389
- https://doi.org//10.1016/j.cub.2008.12.003
- https://doi.org//10.1016/j.gene.2008.02.010
- https://doi.org//10.1534/genetics.103.021675
- https://doi.org//10.1016/j.devcel.2009.12.024
- https://doi.org//10.1145/1745438
- https://doi.org//10.1074/jbc.M111.291104
- https://doi.org//10.4161/cc.24675
- https://doi.org//10.1038/ni.2941
Usage metrics
Read the peer-reviewed publication
Categories
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity