Xu Zhen, Geng Yifei, Guan Lixia, Niu Miao-Miao, Xu Cen, Yang Li, Liang Sudong
Department of Urology, Reproductive Medicine and Oncology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China.
Eur J Med Chem. 2025 Mar 5;285:117248. doi: 10.1016/j.ejmech.2025.117248. Epub 2025 Jan 6.
Cyclin-dependent kinase 9 (CDK9) plays a pivotal role in promoting oncogenic transcriptional pathways, significantly contributing to the development and progression of cancer. Given the unique biostability of d-amino acid, the development of d-amino acid-containing peptides (DAACPs) is a promising strategy for cancer treatment. Currently, no DAACPs inhibitor targeting CDK9-cyclin T1 have been reported. Here, we reported the identification of a novel, highly potent, selective and stable DAACPs inhibitor (peptide-5) targeting CDK9-cyclin T1 interaction. Peptide-5 showed nanomolar inhibitory effect against CDK9-cyclin T1 (IC = 4.16 ± 0.11 nM). Molecular dynamics (MD) simulation exhibited that peptide-5 stably bound to CDK9. Peptide-5 showed good inhibitory activity against multiple types of prostate cancer cells and demonstrated good biostability in mouse serum. Moreover, peptide-5 suppresses the tumor growth in DU145 cell-derived xenografts nude mice. These data suggest that peptide-5 is a potent antitumor candidate for further research.
细胞周期蛋白依赖性激酶9（CDK9）在促进致癌转录途径中起关键作用，对癌症的发生和发展有显著影响。鉴于d-氨基酸独特的生物稳定性，含d-氨基酸的肽（DAACPs）的开发是一种有前景的癌症治疗策略。目前，尚未有针对CDK9-细胞周期蛋白T1的DAACPs抑制剂的报道。在此，我们报告了一种新型、高效、选择性和稳定的靶向CDK9-细胞周期蛋白T1相互作用的DAACPs抑制剂（肽-5）的鉴定。肽-5对CDK9-细胞周期蛋白T1显示出纳摩尔级的抑制作用（IC = 4.16 ± 0.11 nM）。分子动力学（MD）模拟表明肽-5与CDK9稳定结合。肽-5对多种类型的前列腺癌细胞显示出良好的抑制活性，并在小鼠血清中表现出良好的生物稳定性。此外，肽-5抑制DU145细胞衍生的异种移植裸鼠中的肿瘤生长。这些数据表明肽-5是进一步研究的有效抗肿瘤候选物。
