Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis

Xing, Weiman; Ai, Jing; Jin, Shaosheng; Shi, Zhangxing; Xia, Peng; Wang, Lang; Ji, Yinchun; Lu, Dong; Liu, Yang; Geng, Meiyu; Hu, Youhong

doi:10.1016/j.ejmech.2015.03.041

Cited by 30 publications

(11 citation statements)

References 49 publications

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“…In addition, these three pyridazinones were not tested on non-cancerous cells (Ovais et al 2013). Other studies have also published growth inhibitory concentrations (GI 50 , IC 50 ) for other pyridazinone variants, without including non-cancer cell controls, which are important to validate if an experimental compound possesses promising potential as an anti-cancer drug (Elagawany et al 2013; Shunguang et al 2014; Xing et al 2015). Furthermore, these studies were performed by methods that rely on quantifying cell metabolic activity and protein content, such as MTT and SRB assays, respectively, which are indirect approaches to measure cell proliferation or cytotoxicity in cell populations.…”

Section: Discussionmentioning

confidence: 99%

A new pyridazinone exhibits potent cytotoxicity on human cancer cells via apoptosis and poly-ubiquitinated protein accumulation

et al. 2019

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In the last 15 years, pyridazinone derivatives have acquired extensive attention due to their widespread biological activities and pharmacological applications. Pyridazinones are well known for their antimicrobial, anti-viral, anti-inflammatory, anti-cancer, and cardiovascular activities, among others. In this study, we evaluated the anti-cancer activity of a new pyridazinone derivative and propose it as a potential anti-neoplastic agent in acute promyelocytic leukemia cells. Pyr-1 cytotoxicity was assessed on several human cancer and two non-cancerous cell lines by the DNS assay. Pyr-1 demonstrated potent cytotoxicity against 22 human cancer cell lines, exhibiting the most favorable selective cytotoxicity on leukemia (CEM and HL-60), breast (MDA-MB-231 and MDA-MB-468), and lung (A-549) cancer cell lines, when compared with non-cancerous breast epithelial MCF-10A cells. Analyses of apoptosis/necrosis pathways, reactive oxygen species (ROS) production, mitochondria health, caspase-3 activation, and cell cycle profile were performed via flow cytometry. Both hmox-1 RNA and protein expression levels were evaluated by quantitative real-time PCR and Western blotting assays, respectively. Pyr-1 induced apoptosis in acute promyelocytic leukemia cells as confirmed by phosphatidylserine externalization, mitochondrial depolarization, caspase-3 activation, DNA fragmentation, and disrupted cell cycle progression. Additionally, it was determined that Pyr-1 generates oxidative and proteotoxic stress by provoking the accumulation of ROS, resulting in the overexpression of the stress-related hmox-1 mRNA transcripts and protein and a marked increase in poly-ubiquitinated proteins. Our data demonstrate that Pyr-1 induces cell death via the intrinsic apoptosis pathway by accumulating ROS and by impairing proteasome activity.

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Section: Discussionmentioning

confidence: 99%

A new pyridazinone exhibits potent cytotoxicity on human cancer cells via apoptosis and poly-ubiquitinated protein accumulation

et al. 2019

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“…Herein, a selective c-Met inhibitor was fused with HDAC inhibitor pharmacophores to afford a series of hybrid molecules. Previous work by the group revealed the substituent at C7 of the quinoline moiety in the c-Met inhibitor protrudes into the solvent-exposed region of the protein and can tolerate side chain modification with no effect on inhibition and thus served as an attractive position for functionalisation to the HDAC inhibitor [ 87 ]. Enzymatic assays on the preliminary library of compounds revealed o -aminoanilide as the optimal zinc binding group (ZBG) for design of dual HDAC/c-Met inhibitors.…”

Section: Class-i Hdac Dual Inhibitorsmentioning

confidence: 99%

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

2020

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Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics—single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease.

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“…To improve the overall aqueous solubility of a drug, drug development may include the evaluation of the possible addition of hydrophilic moieties to the core structure [121]. This addition of more hydrophilic structures may not be feasible due to the presence of hydrophobic residues that are essential for binding areas of the inhibitors however [122][123][124][125]. Adjustments to the KI chemical structures to improve the biopharmaceutical behavior can therefore only go so far.…”

Section: Essential Structuresmentioning

confidence: 99%