BMS-509744 as Chemical Probe for Studying the Role of Inducible T Cell Kinase in HIV Replication

The chemistry technology section at NCGC has helped the Schwartzberg Group (NHGRI) in its efforts to understand the role of inducible T cell kinase (ITK) in HIV replication. ITK is a Tec-family tyrosine kinases that plays a critical role in integrating pathways important for HIV replication. ITK is expressed in a limited number of cell types including T cells, NK cells, and mast cells. It is also important for TCR-mediated activation of T-cells, where it participates in regulation of PLC³-1, Ca²⁺ mobilization, downstream activation of transcription factors, and actin rearrangement downstream of both TCR and chemokine receptors. 

Since productive infection of T cells with HIV requires T cell activation, chemokine receptors, and actin reorganization, to investigate whether ITK affects HIV infection, the function of ITK needs to be ablated by using ITK-specific siRNA, a kinase-inactive ITK mutant, or a small molecule ITK inhibitor. We synthesized BMS-509744, a potent ITK inhibitor for their study and found that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication.

Key Investigators

National Human Genome research Institute
Pamela Schwartzberg, M.D., Ph.D.

Public Health Impact

This study offers insight into the role that ITK plays in various stages of HIV replication.

Publication

Readinger JA, Schiralli GM, Jiang JK, et al. Selective targeting of ITK blocks multiple steps of HIV replication. PNAS, 2008;105:6684-6689.

Outcomes

The ITK inhibitor BMS-509744 disrupts several aspects of HIV replication.