Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors
Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors
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发现新型吡咯并[2,3-d]嘧啶衍生物作为有效的 JAK/HDAC 双重抑制剂，用于治疗难治性实体瘤
DOI：
10.1021/acs.jmedchem.0c02111
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发表时间：
2022-01-27
影响因子：
7.3
通讯作者：
Liu, Hong
中科院分区：
文献类型：
--
作者：
Liang, Xuewu;Tang, Shuai;Liu, Hong
开发对实体瘤有效的HDAC抑制剂仍然是一个巨大的挑战。以往的研究表明，JAK-STAT3通路的反馈激活是导致乳腺癌对HDAC抑制剂耐药的关键机制，提示JAK/HDAC双重抑制剂具有治疗前景。在这项工作中，我们发现了一系列吡咯并[2，3-d]嘧啶类化合物作为有效的JAK和HDAC双重抑制剂。尤其是化合物15d和15h对三阴性乳腺癌细胞株JAK1/2/3和HDAC1/6有明显的抑制作用，并具有抗增殖和促凋亡作用。此外，化合物15d和15h还减弱了肿瘤相关成纤维细胞触发的LIFR-JAK-STAT信号的激活，这表明这些化合物有可能克服肿瘤微环境造成的耐药性。更重要的是，化合物15d有效地抑制了MDA-MB-231移植瘤模型中的肿瘤生长。总之，这项工作为SAHA耐药的三阴性乳腺癌的治疗提供了有价值的线索和新的抗肿瘤机制。
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.