Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia.
Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia.
复制标题
DOI：
10.1111/bjh.14563
复制
发表时间：
2017-04
影响因子：
6.5
通讯作者：
Look AT
中科院分区：
文献类型：
--
作者：
Akahane K;Li Z;Etchin J;Berezovskaya A;Gjini E;Masse CE;Miao W;Rocnik J;Kapeller R;Greenwood JR;Tiv H;Sanda T;Weinstock DM;Look AT
酪氨酸激酶2（TYK 2）的激活有助于T细胞急性淋巴细胞白血病（T-ALL）细胞的异常存活。在这里，我们证明了一种新型TYK 2抑制剂NDI-031301的抗白血病活性。NDI-031301是一种强效选择性TYK 2抑制剂，可诱导人T-ALL细胞系的稳健生长抑制。NDI-031301处理人T-ALL细胞系导致诱导细胞凋亡，而JAK抑制剂托法替尼和baricitinib未观察到。进一步的研究表明，NDI-031301处理独特地导致三种促分裂原活化蛋白激酶（MAPK）的活化，导致ERK（也称为MAPK 1）、SAPK/JNK（MAPK 9/MAPK 8）和p38 MAPK（MAPK 14）的磷酸化，与PARP裂解一致。p38 MAPK的激活发生在NDI-031301处理的1小时内，并且是NDI-031301诱导的T-ALL细胞死亡的原因，因为p38的药理学抑制部分挽救了TYK 2抑制剂诱导的细胞凋亡。最后，以100 mg/kg bid每日经口给予移植KOPT-K1 T-ALL细胞的免疫缺陷小鼠NDI-031301耐受性良好，并导致肿瘤负荷降低和显著的生存获益。这些结果支持选择性抑制TYK 2作为T-ALL的有希望的潜在治疗策略。
Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK also termed MAPK1), SAPK/JNK (MAPK9/MAPK8) and p38 MAPK (MAPK14) coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL.