Zhang Yonglei, Luo Zhongwen, Jiang Yuhan, Zheng Long, Ma Liangliang, Zheng Yiwei, Zou Meiting, Kong Lingyi, Wang Xiaobing
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Eur J Med Chem. 2025 Jun 5;290:117495. doi: 10.1016/j.ejmech.2025.117495. Epub 2025 Mar 11.
Target of cyclin dependent kinase (CDK) by inhibitors has demonstrated promising potential as a therapeutic agent for cancer. However, the efficacy of monotherapy on tumors is limited and there is an urgent need for combination therapy with other inhibitors. It has been reported that restoring bromodomain-containing protein 4 (BRD4) resensitivity to tumor cells by inhibiting CDK4/6 is a potential therapeutic strategy. In this study, we present the design and optimization of dual CDK4/6 and BRD4 inhibitors, among which B15 exhibited potent and selective inhibition of both targets in vitro, and significant antiproliferative effects in non-small cell lung cancer (NSCLC) cells. Importantly, it also showed good pharmacokinetic properties in rats, meanwhile, B15 effectively inhibited tumor growth in vivo (TGI = 85.3 %) without causing significant toxicity. Overall, our results introduce a promising strategy of dual CDK4/6 and BRD4 inhibitors for the treatment of NSCLC.
细胞周期蛋白依赖性激酶（CDK）抑制剂作为一种癌症治疗药物已显示出有前景的潜力。然而，单一疗法对肿瘤的疗效有限，迫切需要与其他抑制剂联合治疗。据报道，通过抑制CDK4/6恢复含溴结构域蛋白4（BRD4）对肿瘤细胞的敏感性是一种潜在的治疗策略。在本研究中，我们展示了双CDK4/6和BRD4抑制剂的设计与优化，其中B15在体外对两个靶点均表现出强效且选择性的抑制作用，并在非小细胞肺癌（NSCLC）细胞中具有显著的抗增殖作用。重要的是，它在大鼠中也显示出良好的药代动力学特性，同时，B15在体内有效抑制肿瘤生长（肿瘤生长抑制率TGI = 85.3%）且未引起明显毒性。总体而言，我们的结果为双CDK4/6和BRD4抑制剂治疗NSCLC引入了一种有前景的策略。
