J Med Chem
State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
Published: May 2023
A novel series of benzamide derivatives were successively designed and synthesized prepared from the pyridazinone scaffold. Among them, ()-, demonstrated potent inhibitory activity toward human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line. Also, ()- strongly increased the intracellular level of acetyl-histone H3 and P21 simultaneously and effectively induced G1 cell cycle arrest and apoptosis. Through oral dosing in SKM-1 xenograft models, ()- exhibited excellent antitumor activity. In addition, compound ()- showed better antitumor efficacy on mouse models with intact immune system than those with thymus deficiencies. Furthermore, this compound displayed a favorable pharmacokinetic profile in ICR mice and SD rat, respectively, minimal metabolic property differences among hepatocytes from five species, and a low inhibition upon the human ether-a-go-go (hERG) channel with an IC value of 34.6 μΜ. This novel compound ()- may serve as a new drug candidate for further investigation.
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http://dx.doi.org/10.1021/acs.jmedchem.3c00525 | DOI Listing |
T-cell prolymphocytic leukemia (T-PLL) is an aggressive lymphoid malignancy with limited treatment options. To discover new treatment targets for T-PLL, we performed high-throughput drug sensitivity screening on 30 primary patient samples ex-vivo. After screening over 2'800 unique compounds, we found T-PLL to be more resistant to most drug classes, including chemotherapeutics, compared to other blood cancers.
View Article and Find Full Text PDFPLoS One
January 2025
School of Public Health, Anhui University of Science and Technology, Hefei, China.
A number of studies demonstrate the therapeutic effectiveness of Radix Bupleuri (RB) and Hedysarum Multijugum Maxim (HMM) in treating liver fibrosis, but the exact molecular mechanisms remain unclear. This study aims to explore the mechanism of RB-HMM drug pairs in treating liver fibrosis by using network pharmacology, bioinformatics, molecular docking, molecular dynamics simulation technology and in vitro experiments. Totally, 155 intersection targets between RB-HMM and liver fibrosis were identified.
View Article and Find Full Text PDFJ Mater Chem B
January 2025
Drug Delivery, Disposition, and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC, 3052, Australia.
Infections caused by fungal pathogens are a global health problem, and have created an urgent need for new antimicrobial strategies. This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers an optimized Cu(0)-mediated reversible-deactivation radical polymerization (RDRP) approach. Cholesterol-Br was used as an initiator to synthesize a library of oligo-VDM (degree of polymerisation = 5, 10, 15, 20, and 25), with an α-terminal cholesterol group.
View Article and Find Full Text PDFJ Med Virol
February 2025
Department of Microbiology, School of Basic Medicine, Air Force Military Medical University, Xi'an, China.
Virus budding is a critical step in the replication cycle of enveloped viruses, closely linked to viral spread, disease progression, and clinical outcomes. The budding of many enveloped RNA viruses is facilitated by the hijacking of the host endosomal sorting complex required for transport (ESCRT) proteins through viral late domains. These late domains are essential for progeny virus production and are highly conserved, making the interaction between late domains and host ESCRT proteins a potential target for the development of antiviral therapeutics.
View Article and Find Full Text PDFJ Chem Theory Comput
January 2025
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Computer-aided drug discovery (CADD) utilizes computational methods to accelerate the identification and optimization of potential drug candidates. Free energy perturbation (FEP) and thermodynamic integration (TI) play a critical role in predicting differences in protein binding affinities between drug molecules. Here, we implement SPONGE-FEP, which incorporates selective integrated tempering sampling (SITS) to enhance sampling efficiency and contains an automated workflow for relative binding free energy (RBFE) calculations.
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