作者: Pang, Ningning ; Chen, Xing ; Zhao, Na ; Zhu, Huilong ; Huang, Jianhang ; An, Chunmei ; Zhu, Jiayi ; Li, Jian ; Xiong, Xiaochun ; Liang, Guoao ; Wang, Naiyuan

BRD4 serving as an attractive target for the treatment of renal fibrosis has recently received considerable attention. However, to date, the BRD4 inhibitors developed for renal fibrosis treatment were relatively few. Herein, we report the discovery of novel BRD4 inhibitors from virtual screening hit compound 1 with moderate inhibitory activity (IC₅₀ = 7.5 ± 2.9 μM). Through the medicinal chemistry optimization program, leading to the discovery of three potent BRD4 inhibitors, 10, 19 and 31 with IC₅₀ values of 20.0 ± 7.1, 17.5 ± 6.4 and 13.5 ± 4.9 nM, respectively. Among them, 31 showed an acceptable liver microsomal stability and displayed a desired pharmacokinetic profile. Further, we confirmed the therapeutic efficacy of 31 in alleviating renal fibrosis on both UUO and folic acid (FA)-induced renal fibrosis mouse models. Collectively, our results indicated that compound 31 might be a promising candidate for renal fibrosis treatment and deserves further investigations.

2025-06-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Discovery of dual CDK4/6 and BRD4 inhibitor as apoptosis and autophagy inducers against NSCLC in vitro and in vivo

Article

作者: Luo, Zhongwen ; Zheng, Long ; Ma, Liangliang ; Zou, Meiting ; Zhang, Yonglei ; Zheng, Yiwei ; Kong, Lingyi ; Jiang, Yuhan ; Wang, Xiaobing

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.

2025-06-01·PHARMACOLOGICAL RESEARCH

Age-linked DNA methylation and gene expression patterns in parameningeal head and neck alveolar rhabdomyosarcoma reveal CDK9 as a promising therapeutic target

Article

作者: Di Giannatale, Angela ; Alaggio, Rita ; Miele, Evelina ; Cassandri, Matteo ; Russo, Ida ; Barresi, Sabina ; Vallese, Silvia ; Pedace, Lucia ; Locatelli, Franco ; Abballe, Luana ; Vinciarelli, Flavia ; Mancini, Barbara ; Patrizi, Sara ; Stracuzzi, Alessandra ; Rota, Rossella ; Antonacci, Celeste ; Giovannoni, Isabella ; Milano, Giuseppe Maria

BACKGROUND:

Alveolar rhabdomyosarcoma (ARMS) primarily affects children in the first decade of life, but it can also occur during adolescence, typically with a more favorable prognosis. This study aimed to explore differences in DNA methylation (DNAm) and gene expression profiles that may account for the worse prognosis in younger patients; and to investigate possible new therapeutic targets.

METHODS:

We conducted whole-genome DNAm and transcriptome analyses on 10 parameningeal head and neck ARMS patients, including 4 patients under 1 year old and 6 over 10 years old. Among the differentially expressed genes, we focused on actionable therapeutic targets and confirmed their protein expression levels by immunohistochemistry. We validated the biological relevance of molecules of interest through functional experiments on rhabdomyosarcoma cell lines.

RESULTS:

DNAm profiles did not significantly differ across age groups, while gene expression was the primary driver of observed differences. Several enriched pathways characterized younger patients with respect to older ones, including FAS, Integrin, PI3 kinase, and p53 by glucose deprivation. Among actionable molecules, cyclin dependent kinase 9 (CDK9) emerged as a promising therapy target, highly expressed in younger patients. Of note, CDK9 inhibitors specifically inhibit cell growth in bi- and three-dimensional ARMS cellular models, both as a monotherapy and in combination with BRD4 inhibitors.

CONCLUSION:

Despite the small sample size, these findings suggest potential age-related molecular mechanisms and highlight candidate genes for further investigation as novel therapeutic targets. Notably, we identified CDK9 as a promising target, warranting further exploration in the context of ARMS treatment.

100 项与 BRD4 inhibitors(Shanghai Institute of Materia Medica Chinese Academy of Sci) 相关的药物交易

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