Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2169282. doi: 10.1080/14756366.2023.2169282.
To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives was designed, synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.
为了探索细胞周期蛋白依赖性激酶（CDK）抑制剂在胰腺导管腺癌（PDAC）治疗中的潜在用途，设计、合成了一系列新型 2-（（4-磺酰胺基苯基）氨基）-吡咯并[2,3-d]嘧啶衍生物，并研究了它们对 CDK 激酶活性和胰腺癌细胞增殖的抑制作用。大多数新的磺酰胺类衍生物对 CDK9 具有很强的抑制活性，在细胞培养中表现出明显的抗增殖活性。此外，两种新化合物抑制了多种人胰腺癌细胞系的细胞增殖。活性最强的化合物 通过阻断 Rb 磷酸化抑制癌细胞增殖，并通过下调 CDK9 下游蛋白 Mcl-1 和 c-Myc 在 MIA PaCa-2 细胞中诱导细胞凋亡。CDK9 敲低实验表明其抗增殖活性主要是通过 CDK9 介导的。此外， 在 AsPC-1 来源的异种移植小鼠模型中显示出适度的肿瘤抑制作用。总之，这项研究为进一步优化提供了新的起点，以开发单独或联合使用的潜在 CDK 抑制剂候选药物用于 PDAC 治疗。
