Discovery of Novel Pyrrolo[2,3-<i>d</i>]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors
Xuewu Liang, Shuai Tang, Xuyi Liu, Yingluo Liu, Qifu Xu, Xiaomin Wang, Abdusaid Saidahmatov, Chunpu Li, Jiang Wang, Yu Zhou, Yingjie Zhang, Meiyu Geng, Min Huang, Hong Liu
Abstract
It remains a big challenge to develop HDAC inhibitors effective for solid tumors. Previous studies have suggested that the feedback activation of JAK-STAT3 pathway represents a key mechanism leading to resistance to HDAC inhibitors in breast cancer, suggesting the therapeutic promise of JAK/HDAC dual inhibitors. In this work, we discovered a series of pyrrolo[2,3-d]pyrimidine-based derivatives as potent JAK and HDAC dual inhibitors. Especially, compounds 15d and 15h potently inhibited JAK1/2/3 and HDAC1/6 and displayed antiproliferative and proapoptotic activities in triple-negative breast cancer cell lines. Besides, compounds 15d and 15h also diminished the activation of LIFR-JAK-STAT signaling triggered by tumor-associated fibroblasts, which suggests that these compounds could potentially overcome the drug resistance caused by the tumor microenvironment. More importantly, compound 15d effectively inhibited the tumor growth in MDA-MB-231 xenograft tumor model. Overall, this work provides valuable leads and novel antitumor mechanisms for the treatment of the SAHA-resistant triple-negative breast cancers.