366-84-7Relevant articles and documents
Discovery of a Potent Glutathione Peroxidase 4 Inhibitor as a Selective Ferroptosis Inducer
Xu, Congjun,Xiao, Zhanghong,Wang, Jing,Lai, Hualu,Zhang, Tao,Guan, Zilin,Xia, Meng,Chen, Meixu,Ren, Lingling,He, Yuanfeng,Gao, Yuqi,Zhao, Chunshun
, p. 13312 - 13326 (2021/09/28)
Potent and selective ferroptosis regulators promote an intensive understanding of the regulation and mechanisms underlying ferroptosis, which is highly associated with various diseases. In this study, through a stepwise structure optimization, a potent and selective ferroptosis inducer was developed targeting to inhibit glutathione peroxidase 4 (GPX4), and the structure-activity relationship (SAR) of these compounds was uncovered. Compound26aexhibited outstanding GPX4 inhibitory activity with a percent inhibition up to 71.7% at 1.0 μM compared to 45.9% of RSL-3. At the cellular level,26acould significantly induce lipid peroxide (LPO) increase and effectively induce ferroptosis with satisfactory selectivity (the value of 31.5). The morphological analysis confirmed the ferroptosis induced by26a. Furthermore,26asignificantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.
HISTONE DEMETHYLASE INHIBITORS FOR TREATING CANCERS
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Paragraph 0178-0179, (2021/01/22)
The present disclosure provides a new series of 8-hydroxyquinoline derivatives/analogs that are potent KDM4 inhibitors with high activity and selectivity against KDM4 enzymes. Also disclosed are the pharmaceutical compositions comprising such 8-hydroxyqui
Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors
Liu, Wen-Shan,Wang, Rui-Rui,Yue, Hai,Zheng, Zhi-Hui,Lu, Xin-Hua,Wang, Shu-Qing,Dong, Wei-Li,Wang, Run-Ling
, p. 3814 - 3824 (2019/11/03)
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 μM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors. AbbreviationsBBB blood-brain barrierCDC25B cell division cycle 25 homolog BCYP2D6 Cytochrome P450 2D6 bindingDCCM dynamic cross-correlation mapDS Discovery StudioH bond hydrogen bondHIA human intestinal absorptionLAR leukocyte antigen-related phosphataseMD molecular dynamicsMEG-2 maternal-effect germ-cell defective 2MM-PBSA molecular mechanics Poisson Boltzmann surface area)PCA principal component analysisPDB Protein Data BankpNPP p–nitrophenyl phosphatePPB plasma protein bindingPTP1B protein tyrosine phosphotase 1BRMSD root mean square deviationRMSF root mean square fluctuationSHP-1 src homologous phosphatase-1SHP-2 src homologous phosphatase-2SPC single-point chargeTCPTP T cell protein tyrosine phosphataseT2DM Type 2 diabetes mellitusVDW van der Waals Communicated by Ramaswamy H. Sarma.
