Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Bioorg Med Chem. 2021 Jan 1;29:115876. doi: 10.1016/j.bmc.2020.115876. Epub 2020 Nov 17.
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 IC value of 44 nM and potently inhibited cell proliferation in DDR1-overexpressing cell lines HCT-116 and MDA-MB-231 with IC 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，可被三螺旋胶原激活，由于其参与肿瘤生长、转移发展和肿瘤休眠，已成为癌症治疗的一个有吸引力的靶点。一些已上市的药物，如达沙替尼和尼洛替尼，据报道能强有力地抑制 DDR1 的功能，并在多种临床前肿瘤模型中显示出显著的治疗益处。然而，近年来仅披露了少数几种选择性 DDR1 抑制剂。我们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增殖抑制试验进行评估。代表性化合物 6c 对 DDR1 激酶活性的抑制 IC 值为 44 nM，并对 DDR1 过表达的 HCT-116 和 MDA-MB-231 细胞系具有强大的抑制增殖作用，IC 值分别为 4.00 和 3.36 μM。进一步的分子对接研究表明，6c 理想地适合 DDR1 结合口袋，并与 DDR1 激酶结构域保持关键氢键。总之，这些结果表明，化合物 6c 是一种有潜力的 DDR1 抑制剂，值得进一步研究用于癌症治疗。
