Huang, Zhi; Zhou, Wei; Li, Yongtao; Cao, Mei; Wang, Tianqi; Ma, Yakun; Guo, Qingxiang; Wang, Xin; Zhang, Chao; Zhang, Chenglan; Shen, Wenzhi; Liu, Yanhua; Chen, Yanan; Zheng, Jianyu; Yang, Shengyong; Fan, Yan; Xiang, Rong published the artcile< Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling>, Reference of 220731-04-4, the main research area is breast ovarian cancer HDAC inhibitor JAK1 STAT3 BCL2 signaling; CDK4/6; HDAC1; JAK1; inhibitor; solid tumour.
Despite initial progress in preclin. models, most known histone deacetylase inhibitors (HDACis) used as a single agent have failed to show clin. benefits in nearly all types of solid tumors. Hence, the efficacy of HDACis in solid tumors remains uncertain. Herein, we developed a hybrid HDAC inhibitor that sensitized solid tumors to HDAC-targeted treatment. Methods: A hybrid mol., Roxyl-zhc-84 was designed and synthesized with novel architecture. The pharmacokinetics and toxicity of Roxyl-zhc-84 were analyzed. Results: Roxyl-zhc-84 showed excellent pharmacokinetics and low toxicity. The novel hybrid inhibitor Roxyl-zhc-84 induced cell apoptosis and G1-phase arrest in breast cancer and ovarian cancer cell lines. In three mouse models, oral administration of Roxyl-zhc-84 led to significant tumor regression without obvious toxicity. Moreover, Roxyl-zhc-84 dramatically improved the limited response of traditional HDAC inhibitors in solid tumors via overcoming JAK1-STAT3-BCL2-mediated drug resistance. Roxyl-zhc-84 treatment exhibited vastly superior efficacy than the combination of HDAC and JAK1 inhibitors both in vitro and in vivo. Conclusion: Concurrent inhibition of HDAC and CDK using Roxyl-zhc-84 with addnl. JAK1 targeting resolved the limited response of traditional HDAC inhibitors in solid tumors via overcoming JAK1-STAT3-BCL2-mediated drug resistance, providing a rational multi-target treatment to sensitize solid tumors to HDACi therapy.
Theranostics published new progress about Acetylated histone H3 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 220731-04-4 belongs to class pyridine-derivatives, and the molecular formula is C10H15N3O2, Reference of 220731-04-4.