Song Peiran, Bai Gang, Chan Shingpan, Zhang Tao, Tong Linjiang, Su Yi, Shen Yanyan, Chen Yi, Liu Yingqiang, Lai Mengzhen, Ning Yi, Tang Haotian, Fang Yan, Chen Yi, Ding Ke, Ding Jian, Xie Hua
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Front Pharmacol. 2022 Dec 15;13:1071114. doi: 10.3389/fphar.2022.1071114. eCollection 2022.
Hyperactivation of Bruton's tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets for the treatment of hematological malignancies. We identified a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, ASK120067 (limertinib) in our previous research, which has been applied as a new drug application against non-small cell lung cancer in China. In this work, we found that ASK120067 displayed potent inhibitory efficacy against Bruton's tyrosine kinase protein and interleukin-2-inducible T cell kinase protein covalent binding. In cell-based assays, ASK120067 dose-dependently suppressed Bruton's tyrosine kinase phosphorylation and exhibited anti-proliferation potency by inducing apoptosis in numerous B-lymphoma cells. Meanwhile, it caused growth arrest and induced the apoptosis of T-cell leukemia cells by attenuating interleukin-2-inducible T cell kinase activation. Oral administration of ASK120067 led to significant tumor regression in B-cell lymphoma and T-cell leukemia xenograft models by weakening Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase signaling, respectively. Taken together, our studies demonstrated that ASK120067 exerted preclinical anti-tumor activities against B-/T-cell malignancy by targeting BTK/ITK.
布鲁顿酪氨酸激酶（BTK）或白细胞介素-2诱导型T细胞激酶（ITK）的过度激活分别被认为是B细胞淋巴瘤或T细胞白血病发病机制的原因，这表明布鲁顿酪氨酸激酶和白细胞介素-2诱导型T细胞激酶是治疗血液系统恶性肿瘤的关键靶点。在我们之前的研究中，我们鉴定了一种新型的第三代表皮生长因子受体（EGFR）抑制剂ASK120067（利美替尼），它在中国已作为抗非小细胞肺癌的新药申请。在这项工作中，我们发现ASK120067对布鲁顿酪氨酸激酶蛋白和白细胞介素-2诱导型T细胞激酶蛋白共价结合具有强大的抑制作用。在基于细胞的实验中，ASK120067剂量依赖性地抑制布鲁顿酪氨酸激酶磷酸化，并通过诱导多种B淋巴瘤细胞凋亡表现出抗增殖能力。同时，它通过减弱白细胞介素-2诱导型T细胞激酶的激活导致T细胞白血病细胞生长停滞并诱导其凋亡。口服ASK120067分别通过减弱布鲁顿酪氨酸激酶和白细胞介素-2诱导型T细胞激酶信号传导，导致B细胞淋巴瘤和T细胞白血病异种移植模型中的肿瘤显著消退。综上所述，我们的研究表明ASK120067通过靶向BTK/ITK对B/T细胞恶性肿瘤发挥临床前抗肿瘤活性。
