TY - JOUR
T1 - Screening serine/threonine and tyrosine kinase inhibitors for histidine kinase inhibition
AU - Wilke, Kaelyn E.
AU - Fihn, Conrad A.
AU - Carlson, Erin E.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/10/15
Y1 - 2018/10/15
N2 - Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP-binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development.
AB - Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP-binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development.
KW - Antibacterial targets
KW - Histidine kinases
KW - Inhibitors
KW - Roche Published Kinase Set
KW - Two-component systems
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U2 - 10.1016/j.bmc.2018.04.047
DO - 10.1016/j.bmc.2018.04.047
M3 - Article
C2 - 29706527
AN - SCOPUS:85046167543
SN - 0968-0896
SP - 5322
EP - 5326
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
ER -