Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells

Song, Yoojin; Park, Sun You; Wu, Zhexue; Liu, Kwang-Hyeon; Seo, Young Ho

doi:10.1080/14756366.2020.1754812

Cited by 6 publications

(9 citation statements)

References 51 publications

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“…The MEK inhibitor selumetinib has shown anti-tumour effects in EC cell culture [ 201 ], whilst binimetinib is yet to be studied in EC. The chemotherapy agents chlorambucil, carmustine and bendamustine are frequently used in the treatment of haematological cancers, such as non-Hodgkin lymphoma and chronic lymphocytic leukaemia, but are yet to be studied in EC [ 202 , 203 , 204 , 205 ]. Our data also identified many novel drug agents that demonstrate anti-tumour activity in vitro and in vivo, and these include the anti-mesothelin immunotoxin SS1 (dsFv)-PE38, the PI3K inhibitor AZD-6482 and the cyclin-dependent kinase inhibitors variolin B, meriolin, alsterpaullone and dinaciclib [ 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 ].…”

Section: Discussionmentioning

confidence: 99%

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

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Hill

et al. 2020

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Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.

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Section: Discussionmentioning

confidence: 99%

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

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Hill

et al. 2020

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“…The inhibitory effects of KS15 and compound 5d on the metabolism of five cytochrome P450 (P450) probe substrates were evaluated using previous methods with slight modifications [ 19 , 20 ]. The following P450 probe substrates were used: phenacetin (100 μM) for CYP1A2, tolbutamide (100 μM) for CYP2C9, omeprazole (20 μM) for CYP2C19, dextromethorphan (5 μM) for CYP2D6, and midazolam (5 μM) for CYP3A.…”

Section: Methodsmentioning

confidence: 99%

Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement

et al. 2021

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Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an attractive therapeutic target with novel mechanisms of action. Based on the previous structure–activity relationship study of small molecule cryptochrome (CRY) inhibitors possessing an ethoxypropanoic acid moiety, non-ethoxypropanoic acid-type inhibitors have been developed by bioisosteric replacement. They were evaluated as potent and effective enhancers of E-box-mediated transcription, and, in particular, ester 5d and its hydrolysis product 2d exhibited desirable metabolic and pharmacokinetic profiles as promising drug candidates. Compound 2d directly bound to both CRY1 and 2 in surface plasmon resonance analyses, suggesting that the molecular target is CRY. Effects of compound 5d and 2d on suppressive action of CRY1 on CLOCK:BMAL1-activated E-box-LUC reporter activity revealed that both compounds inhibited the negative feedback actions of CRY on CLOCK:BMAL1. Most importantly, compounds 5d and 2d exhibited significant effects on molecular circadian rhythmicity to be considered circadian clock-enhancers, distinct from the previously developed CRY inhibitors possessing an ethoxypropanoic acid moiety.

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“…Song et al prepared Chlorambucil-hydroxamic acid hybrid compound 22 (Figure 16) [45]. The synthesized hybrid compound 22 was evaluated for its anticancer effect against several human cancer cell lines, including two breast cancer cell lines (MCF-7 and MDA-MB-231), two leukaemia cell lines (U-937 and HL-60), and one ovarian (A2780) cancer cell line [45]. It exhibited superior antiproliferative activity compared to Chlorambucil against the human leukaemia cancer cells.…”

Section: Chlorambucil Hybridized With Dna/ Hdac Inhibitorsmentioning

confidence: 99%

“…Hybrid 22 was not toxic to normal cells. Therefore, it can be a better agent for the treatment of cancer [45].…”

Section: Chlorambucil Hybridized With Dna/ Hdac Inhibitorsmentioning

confidence: 99%

Chlorambucil-Bearing Hybrid Molecules in the Development of Potential Anticancer Agents

Peter,

Aderibigbe

2023

Molecules

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Increasing cases of cancer have been a primary concern in recent decades. Developing new chemotherapeutics is challenging and has been faced with limitations, such as multidrug resistance, poor specificity, selectivity, and toxicity. The aforementioned factors contribute to treatment failure. Hybrid compounds have features that can overcome the limitations mentioned above. Chlorambucil, an anticancer drug that is used to treat prostate and breast cancer, suffers from poor aqueous solubility and specificity, a short half-life, and severe side effects, including anaemia and bone marrow suppression. It compromises the immune system, resulting in treatment failure. Hence, its combination with other pharmacophores has been reported to result in effective anticancer agents with fewer side effects and high therapeutic outcomes. Furthermore, this review gives an update (2010 to date) on the developments of chlorambucil hybrid compounds with anticancer activity, and the structure-activity relationship (SAR), and also highlights future strategies for developing novel anticancer agents.

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Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells

Cited by 6 publications

References 51 publications

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement

Chlorambucil-Bearing Hybrid Molecules in the Development of Potential Anticancer Agents

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