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Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-10-05 , DOI: 10.1021/acs.jmedchem.3c01242
Chunlong Zhao 1 , Yu Zhang 2 , Jin'ge Zhang 2 , Shunda Li 1 , Mengyang Liu 2 , Yinping Geng 2 , Fengling Liu 1 , Qipeng Chai 1 , Hongwei Meng 1 , Mengzhe Li 1 , Jintao Li 1 , Yichao Zheng 2 , Yingjie Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-10-05 , DOI: 10.1021/acs.jmedchem.3c01242
Chunlong Zhao 1 , Yu Zhang 2 , Jin'ge Zhang 2 , Shunda Li 1 , Mengyang Liu 2 , Yinping Geng 2 , Fengling Liu 1 , Qipeng Chai 1 , Hongwei Meng 1 , Mengzhe Li 1 , Jintao Li 1 , Yichao Zheng 2 , Yingjie Zhang 1
Affiliation
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Multitarget HDAC inhibitors capable of simultaneously blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based multitarget HDAC inhibitors were rationally designed, synthesized, and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3 signaling pathway, which was validated by hyper-acetylation of histone and α-tubulin, hypo-phosphorylation of STAT3, downregulation of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects of 25ap contributed to its robust antitumor response, including potent antiproliferative activity, remarkable apoptosis-inducing activity, and inhibition of colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous cells, desirable in vitro metabolic stability in mouse microsome, and sufficient in vivo exposure via intraperitoneal administration. Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft model.
中文翻译:
发现新型基于 Fedratinib 的 HDAC/JAK/BRD4 三重抑制剂,对三阴性乳腺癌具有显着的抗肿瘤活性
能够同时阻断 BRD4-LIFR-JAK1-STAT3 信号通路的多靶点 HDAC 抑制剂在治疗 TNBC 和其他实体瘤方面具有巨大潜力。在此,合理设计、合成和生物学评估了基于Fedratinib的新型多靶点HDAC抑制剂,其中化合物25a p作为有效的HDAC/JAK/BRD4三重抑制剂脱颖而出。令人满意的是,化合物25a p导致 HDAC 和 BRD4-LIFR-JAK1-STAT3 信号通路的同时抑制,这通过组蛋白和 α-微管蛋白的过度乙酰化、STAT3 的低磷酸化、LIFR、MCL-1 的下调得到验证。和 MDA-MB-231 细胞中的 c-Myc。25a p的多靶点效应有助于其强大的抗肿瘤反应,包括有效的抗增殖活性、显着的细胞凋亡诱导活性和抑制集落形成。值得注意的是,25a p在正常细胞和癌细胞之间具有可接受的治疗窗口,在小鼠微粒体中具有理想的体外代谢稳定性,并且通过腹膜内给药获得足够的体内暴露。此外, 25a p的体内抗肿瘤效力在 MDA-MB-231 异种移植模型中得到了证明。
更新日期:2023-10-05
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
发现新型基于 Fedratinib 的 HDAC/JAK/BRD4 三重抑制剂,对三阴性乳腺癌具有显着的抗肿瘤活性
能够同时阻断 BRD4-LIFR-JAK1-STAT3 信号通路的多靶点 HDAC 抑制剂在治疗 TNBC 和其他实体瘤方面具有巨大潜力。在此,合理设计、合成和生物学评估了基于Fedratinib的新型多靶点HDAC抑制剂,其中化合物25a p作为有效的HDAC/JAK/BRD4三重抑制剂脱颖而出。令人满意的是,化合物25a p导致 HDAC 和 BRD4-LIFR-JAK1-STAT3 信号通路的同时抑制,这通过组蛋白和 α-微管蛋白的过度乙酰化、STAT3 的低磷酸化、LIFR、MCL-1 的下调得到验证。和 MDA-MB-231 细胞中的 c-Myc。25a p的多靶点效应有助于其强大的抗肿瘤反应,包括有效的抗增殖活性、显着的细胞凋亡诱导活性和抑制集落形成。值得注意的是,25a p在正常细胞和癌细胞之间具有可接受的治疗窗口,在小鼠微粒体中具有理想的体外代谢稳定性,并且通过腹膜内给药获得足够的体内暴露。此外, 25a p的体内抗肿瘤效力在 MDA-MB-231 异种移植模型中得到了证明。