AUTHOR=Chen Elijah W. , Tay Neil Q. , Brzostek Joanna , Gascoigne Nicholas R. J. , Rybakin Vasily 

TITLE=A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01718

DOI=10.3389/fimmu.2019.01718

ISSN=1664-3224

ABSTRACT=<p>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.</p>