Figure 2
From: Identification of kinase inhibitors as potential host-directed therapies for intracellular bacteria
Identification of HDT targets against intracellular Stm through combined chemical and genetic inhibition of host kinases. (a) Each circle in the phylogenetic tree depicts host kinases that are relevant for HDT against intracellular Stm by combining data from chemical19,20 and genetic6 kinase inhibition screens. The effect of chemical inhibition of kinase targets is represented by circle size, which corresponds to the number of Stm hit compounds that inhibit a kinase by > 50%51. The effect of genetic inhibition of kinase targets, using a siRNA knockdown screen of host kinases in Stm-infected HeLa cells, is shown by color. The most relevant targets for Stm survival are shown in green, while likely off-targets are shown in black. White circles represent targets for which genetic inhibition data were not available. (b) All 11 Stm hit compounds were clustered according to chemotype and chemical similarity, using the Tanimoto coefficient as a similarity measure with cut-off value of 0.551. (c) Chemical structures of the 2-anilino-4-pyrrolidinopyrimidine Stm hit compounds GSK1379738A and GSK1379760A. (d) The level of inhibition of kinase targets shared by GSK1379760A and GSK1379738A at 1 μM. (e) Effect of knockdown of JAK2 and AAK1 on the bacterial burden of Stm-infected HeLa cells. (f) Chemical structures of the 4-anilinoquinoline Stm hit compounds GW557777X and GW560116X. (g) The level of inhibition of kinase targets shared by GW557777X and GW560116X at 1 μM. (h) Effect of knockdown of the same kinase targets on the bacterial burden of Stm-infected HeLa cells.
