ITK Degradation to Block T-cell Receptor Signaling and Overcome Therapeutic Resistance in T-Cell Lymphomas

IL-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T-cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently 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 T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. 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 T cell-mediated diseases. NSG mice were xenografted with H9 cells and treated with vehicle control or BSJ-05-037 (50 mg/kg I.P., Q.O.D) for for 14 days.

白细胞介素-2诱导性T细胞激酶（IL-2-inducible T cell kinase, ITK）对T细胞受体（T cell receptor, TCR）信号传导至关重要，在T细胞增殖与分化过程中发挥不可或缺的作用。与ITK的同源蛋白布鲁顿酪氨酸激酶（Bruton's tyrosine kinase, BTK）不同，目前尚无ITK抑制剂获得美国食品药品监督管理局（Food and Drug Administration, FDA）批准。此外，近期研究已在BTK中发现可同时对共价抑制剂与非共价抑制剂产生耐药性的突变。本研究作为一种替代策略，报道了强效高选择性ITK异双功能降解剂BSJ-05-037的开发工作。相较于其母体抑制剂BMS-509744，BSJ-05-037展现出更优异的抗增殖活性，可阻断核因子κB（NF-κB）/GATA结合蛋白3（GATA-3）信号通路的激活，并在体外与体内实验中均能提升T细胞淋巴瘤细胞对细胞毒性化疗的敏感性。综上，靶向降解ITK是一种调控TCR信号强度的全新策略，有望在T细胞介导性疾病的研究与治疗中获得广泛应用。本研究将H9细胞异种移植至NSG小鼠体内，随后分别以溶媒对照或BSJ-05-037（50 mg/kg，腹腔注射，隔日一次）处理小鼠，持续14天。