130029-61-7Relevant articles and documents
Potent Hydrazide-Based HDAC Inhibitors with a Superior Pharmacokinetic Profile for Efficient Treatment of Acute Myeloid Leukemia in Vivo
Chi, Dongyu,Chou, C. James,Hou, Xiaohan,Huang, Chao,Jiang, Yuqi,Li, Min,Li, Xiaoyang,Qin, Mengting,Xu, Jie,Xu, Tongqiang,Yu, Qixin,Yue, Kairui,Zhu, Yue
, (2022/01/11)
As "Michael acceptors"may induce promiscuous responses in mammalian cells by reacting with various proteins, we modified the cinnamamide of our previous hydrazide-based HDAC inhibitors (HDACIs) to deactivate the Michael reaction. Representative compound 11h is 2-5 times more potent than lead compound 17 in both HDAC inhibitory activity (IC50 = 0.43-3.01 nM) and cell-based antitumor assay (IC50 = 19.23-61.04 nM). The breakthrough in the pharmacokinetic profile of 11h (oral bioavailability: 112%) makes it a lead-in-class oral active agent, validated in the in vivo anti-AML study (4 mg/kg p.o., TGI = 78.9%). Accumulated AcHH3 and AcHH4 levels in tumor tissue directly correlate with the in vivo efficacy, as panobinostat with lower AcHH3 and AcHH4 levels than 11h displays limited activity. To the best of our knowledge, this work contributes the first report of in vivo antitumor activity of hydrazide-based HDACIs. The outstanding pharmacokinetic/pharmacodynamic and antitumor activity of 11h could potentially extend the clinical application of current HDACIs.
PHOTOPROXIMITY PROFILING OF PROTEIN-PROTEIN INTERACTIONS IN CELLS
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Page/Page column 73, (2021/04/01)
Photoactive probes and probe systems for detecting biological interactions are described. The photoactive probes include probes that combine both photocleavable and photoreactive moieties. The photoactive probe systems can include a first probe comprising a photocatalytic group and a second probe comprising a group that can act as a substrate for the reaction catalyzed by the photocatalytic group. The probes and probe systems can also include groups that can specifically bind to a binding partner on a biological entity of interest and a detectable group or a precursor thereof. The probes and probe systems can detect spatiotemporal interactions of proteins or cells. In some embodiments, the interactions can be detected in live cells. Also described are methods of detecting the biological interactions.
Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups
Gao, Shuai,Zang, Jie,Gao, Qianwen,Liang, Xuewu,Ding, Qinge,Li, Xiaoyang,Xu, Wenfang,Chou, C. James,Zhang, Yingjie
, p. 2981 - 2994 (2017/05/25)
As a hot topic of epigenetic studies, histone deacetylases (HDACs) are related to lots of diseases, especially cancer. Further researches indicated that different HDAC isoforms played various roles in a wide range of tumor types. Herein a novel series of HDAC inhibitors with isatin-based caps and o-phenylenediamine-based zinc binding groups have been designed and synthesized through scaffold hopping strategy. Among these compounds, the most potent compound 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat (MS-275). Additionally, compared with MS-275 (IC50 values for HDAC1, 2 and 3 were 0.163, 0.396 and 0.605?μM, respectively), compound 9n with IC50 values of 0.032, 0.256 and 0.311?μM for HDAC1, 2 and 3 respectively, showed a moderate HDAC1 selectivity.
