Abstract

The Src homology 2 (SH2) domain plays a pivotal role in phosphotyrosine (pTyr) signaling pathway. Our recent study showed that a majority of SH2 domains tightly bind lipids in the plasma membrane (PM) using a cationic site separate from the pTyr pocket, which is essential for their cellular protein‐protein interactions. To test the feasibility of modulating pTyr signaling activity by controlling SH2 domain‐lipid binding, we screened and optimized small molecule inhibitors for SH2 domain‐lipid binding. Small molecule inhibitors of the SH2 domain of spleen tyrosine kinase (Syk), which plays a key role in B cell signaling and has high affinity for PM, caused potent and specific inhibition of Syk signaling activities in DT40 B cells while exhibiting minimal activity against ZAP70 in Jurkat T cells.Support or Funding InformationNIH GM68849

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