LAUSR

Cutaneous T cell lymphomas (CTCLs) comprise a heterogeneous group of uncommon non-Hodgkin lymphomas with primary manifestations in the skin [1]. Though CTCL treatment strategies are rapidly evolving, novel CTCL-targeted therapies are still needed, especially for patients with advanced disease. Highly targeted therapies have been developed for other immune system malignancies. For example, Bruton’s tyrosine kinase (BTK) is implicated in the development of a variety of B-cell malignancies [2] and the targeted BTK inhibitor, ibrutinib, is now FDA approved for treatment of mantle cell lymphoma and chronic lymphocytic leukemia [3]. Although the cause of CTCL is variable, genetic studies have revealed that this cancer acquires mutations that promote T cell growth and survival; however, no single mutation is present in the majority of patients [4]. Therefore, rather than targeting a specific mutation, broad inhibition of T cell-specific signaling is a promising therapeutic approach for CTCL. Like Bruton’s tyrosine kinase (BTK), the IL-2-inducible Tcell kinase (ITK) (Fig. 1A) is a member of the Tec family of non-receptor protein tyrosine kinases. Tec kinases, like BTK and ITK, help to transduce signals originating from cell surface receptors. ITK is directly downstream of LCK in the T cell receptor (TCR)-mediated signal transduction cascade. It plays an important role in T cell activation, proliferation, differentiation, and effector cytokine production [5] (Fig. 1A). In contrast to BTK, ITK inhibitors have not been extensively studied for their anti-cancer properties, but it is known that ITK is expressed in all T cell malignancies, including CTCL. Because ITK is only expressed by T cells, NKT cells, and to a much lesser extent, mast cells, ITK-targeted therapy would be highly specific for T cell malignancies. Herein we demonstrate that ITK inhibition is a potential avenue for the development of CTCLtargeted therapies. Through screening a 9600-diversity combinatorial solutionphase small-molecule library, compounds with inhibitory activities against ITK were isolated. Subsequent molecular modeling and extensive structure-activity relationship studies led to the identification of CTA191 (Fig. 1B). Docking studies of CTA191 with ITK indicate that CTA191 binds well to the kinase domain of ITK, fitting into the ATP-binding pocket (Fig. 1C). Binding appears to be mediated through hydrogen bonds and p-p hydrophobic interactions with residues in the ATP-binding pocket (Fig. 1C). The synthetic scheme of CTA191 is depicted in Fig. 1B. Following inhibitor-kinase molecular modeling studies, kinase specificities were directly tested in vitro for the most promising ITK