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 IC₅₀ value of 4.00 and 3.36 μM 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.

DDR1 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点。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 DDR1 的功能，并在各种临床前肿瘤模型中显示出显着的治疗效果。而近年来仅公开了少数选择性 DDR1 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。所有化合物均通过 DDR1 激酶抑制试验和细胞抗增殖试验进行评估。代表性化合物之一，6c，抑制 DDR1 激酶活性，IC ₅₀值为 44 nM，有效抑制 DDR1 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 μM。进一步的分子对接研究表明，6c非常适合 DDR1 结合口袋，并保持与 DDR1 激酶结构域的关键氢键。总体而言，这些结果表明化合物6c是一种潜在的 DDR1 抑制剂，值得进一步研究用于癌症治疗。