Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, P.R. China.
Key Lab of Advanced Drug Preparation Technologies (Ministry of Education), State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China.
J Med Chem. 2023 Oct 26;66(20):14150-14174. doi: 10.1021/acs.jmedchem.3c01242. Epub 2023 Oct 5.
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 stood out as a potent HDAC/JAK/BRD4 triple inhibitor. Satisfyingly, compound 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 contributed to its robust antitumor response, including potent antiproliferative activity, remarkable apoptosis-inducing activity, and inhibition of colony formation. Notably, 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 was demonstrated in an MDA-MB-231 xenograft model.
多靶点 HDAC 抑制剂能够同时阻断 BRD4-LIFR-JAK1-STAT3 信号通路，在治疗三阴性乳腺癌和其他实体瘤方面具有巨大潜力。在此，我们合理设计、合成并对新型 Fedratinib 为基础的多靶点 HDAC 抑制剂进行了生物学评估，其中化合物脱颖而出，成为一种有效的 HDAC/JAK/BRD4 三重抑制剂。令人满意的是，化合物导致 HDAC 和 BRD4-LIFR-JAK1-STAT3 信号通路的同时抑制，这通过组蛋白和α-微管蛋白的超乙酰化、STAT3 的低磷酸化、LIFR、MCL-1 和 c-Myc 在 MDA-MB-231 细胞中的下调得到验证。化合物的多靶点作用有助于其强大的抗肿瘤反应，包括强大的抗增殖活性、显著的诱导凋亡活性和抑制集落形成。值得注意的是，化合物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良好的体外代谢稳定性，并且通过腹腔给药具有足够的体内暴露量。此外，在 MDA-MB-231 异种移植模型中证明了化合物的体内抗肿瘤效力。
