ITK degradation to block T cell receptor signaling and overcome therapeutic resistance in T cell lymphomas

Abstract

Interleukin (IL)-2-inducible Tcell kinase (ITK) is essential for Tcell receptor (TCR) signaling and plays an integral role in Tcell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug Administration (FDA) approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of Tcell lymphoma cells to cytotoxic chemotherapy both invitro and invivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of Tcell-mediated diseases.