SYK-specific tyrosine kinase inhibitors

 

Syk is a tyrosine kinase whose activity regulates most hematopoietic cells and whose expression is largely confined to these blood cells. Not surprisingly, SYK mediated phosphorylation of its protein substrates is also involved in many hematopoietic pathologies, including sickle cell disease, leukemias, lymphomas, malaria, autoimmune diseases, and even Alzheimer’s disease. Because all SYK inhibitors to date exhibit significant off-target efficacy against many other tyrosine kinases, their use in treating the above pathologies has invariably been accompanied by undesirable toxicities. We have designed several SYK kinase inhibitors that are nearly devoid of activity against other tyrosine kinases, rendering them very useful for treating the above diseases. Studies are underway to select an optimal indication for evaluating its safety and efficacy in humans. In sickle cell disease, an over-active SYK phosphorylates protein 3 in the above sketch of an RBC membrane, leading to dissociation of the spectrin/actin cytoskeleton from the membrane and the cell fragmentation. The consequent release of hemoglobin and membrane fragments triggers the vaso-occlusive events that ultimately cause sickle cell disease.