Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer

Abstract

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 <b>25a</b><i><b>p</b></i> stood out as a potent HDAC/JAK/BRD4 triple inhibitor. Satisfyingly, compound <b>25a</b><i><b>p</b></i> 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 <b>25a</b><i><b>p</b></i> contributed to its robust antitumor response, including potent antiproliferative activity, remarkable apoptosis-inducing activity, and inhibition of colony formation. Notably, <b>25a</b><i><b>p</b></i> 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 <b>25a</b><i><b>p</b></i> was demonstrated in an MDA-MB-231 xenograft model.