Discovery of 3,5-Diamino-1,2,4-triazole Ureas as Potent Anaplastic Lymphoma Kinase Inhibitors

A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.

本研究发现一系列新型3,5-二氨基-1,2,4-三唑苄基脲类化合物具有强效的间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）抑制活性，其中代表性化合物15a、20a及23a在Tel-ALK转化的Ba/F3细胞中展现出的抗增殖半最大效应浓度（IC50）分别为70 nM、40 nM及20 nM。此外，化合物15a与23a可强效抑制NPM-ALK阳性间变性大细胞淋巴瘤细胞（SU-DHL-1）以及携带F1174L型ALK突变的神经母细胞瘤细胞系（KELLY、SH-SY5Y）的生长与存活。此类化合物为用于癌症治疗的小分子ALK抑制剂的开发提供了全新的先导化合物。