Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation 
with downstream signaling pathways, affecting cell survival and proliferation. 
Moreover, Syk is involved in BCR-independent functions, such as B-cell migration 
and adhesion. In chronic lymphocytic leukemia (CLL), Syk becomes activated by 
external signals from the tissue microenvironment, and was targeted in a first 
clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor. 
Here, we characterize the activity of two novel, highly selective Syk 
inhibitors, PRT318 and P505-15, in assays that model CLL interactions with the 
microenvironment. PRT318 and P505-15 effectively antagonize CLL cell survival 
after BCR triggering and in nurse-like cell-co-cultures. Moreover, they inhibit 
BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and 
leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and 
beneath stromal cells. PRT318 and P505-15 furthermore inhibit Syk and 
extracellular signal-regulated kinase phosphorylation after BCR triggering. 
These findings demonstrate that the selective Syk inhibitors PRT318 and P505-15 
are highly effective for inhibition of CLL survival and tissue homing circuits, 
and support the therapeutic development of these agents in patients with CLL, 
other B-cell malignancies and autoimmune disorders.