Discovery of 4-amino-1H-pyrazolo [3,4-d] pyrimidin derivatives as novel discoidin domain receptor 1 (DDR1) inhibitors
Discovery of 4-amino-1H-pyrazolo [3,4-d] pyrimidin derivatives as novel discoidin domain receptor 1 (DDR1) inhibitors
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DOI：
10.1016/j.bmc.2020.115876
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发表时间：
2021-01-01
影响因子：
3.5
通讯作者：
Sun, Li-Ping
中科院分区：
文献类型：
--
作者：
Dong, Ru;Zhou, Xin;Sun, Li-Ping
DDR 1是一种受体酪氨酸激酶，由三螺旋胶原蛋白激活，由于其参与肿瘤生长、转移发展和肿瘤休眠，已成为抗癌治疗的有吸引力的靶标。据报道，市场上的几种药物，如达沙替尼和尼洛替尼，可有效抑制DDR 1的功能，并在各种临床前肿瘤模型中显示出显著的治疗益处。而近年来仅公开了少数选择性DDR 1抑制剂。设计并合成了一系列4-氨基-1H-吡唑并[3，4-d]嘧啶衍生物。通过DDR 1激酶抑制试验和细胞抗增殖试验评价所有化合物。代表性化合物之一6c抑制DDR 1激酶活性，IC 50值为44 nM，并有效抑制DDR 1过表达细胞系HCT-116和MDA-MB-231中的细胞增殖，IC（50）值分别为4.00和3.36 μ M。进一步的分子对接研究表明，6c与DDR 1结合口袋非常匹配，并保持了与DDR 1激酶结构域的关键氢键。总之，这些结果表明化合物6c是一种潜在的DDR 1抑制剂，值得进一步研究用于癌症治疗。
DDR1 is a receptor tyrosine kinase that is activated by triple-helical collagens and has become an attractive target for anticancer therapy given its involvement in tumor growth, metastasis development, and tumor dormancy. Several drugs on the market, such as dasatinib and nilotinib, were reported to potently suppress the function of DDR1 and show significant therapeutic benefits in a variety of preclinical tumor models. Whereas only a few selective DDR1 inhibitors were disclosed in recent years. A series of 4-amino-1H-pyrazolo [3,4-d] pyrimidin derivatives were designed and synthesized. All compounds were evaluated via DDR1 kinase inhibition assay and cell anti-proliferative assay. One of the representative compounds, 6c, suppressed DDR1 kinase activity with an IC50 value of 44 nM and potently inhibited cell proliferation in DDR1-overexpressing cell lines HCT-116 and MDA-MB-231 with IC(50 )value of 4.00 and 3.36 mu M respectively. Further molecular docking study revealed that 6c fitted ideally into DDR1 binding pocket and maintained the crucial hydrogen bonds with DDR1 kinase domain. Overall, these results suggest that the compound 6c is a potential DDR1 inhibitor deserving further investigation for cancer treatment.