The discovery of a novel compound with potent antitumor activity: virtual screening, synthesis, biological evaluation and preliminary mechanism study

Jin, Yuanyuan; Li, Linhu; Yang, Zhaoyong; Liu, Mingliang; Guo, Hai‐Ming; Shen, Weiyi

doi:10.18632/oncotarget.15601

Cited by 11 publications

(2 citation statements)

References 29 publications

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“…The -CDOCKER Interaction Energy (CIE) of DPP4 and the above active ingredients was 52.6, 50.6, 49.5, 47.4, and 47.4 kcal/mol ( Figure 4B ). According to previous publications on drug-protein interactions, compounds with -CIE of approximately 50 kcal/mol can be used as effect moles for their putative targets ( Li et al, 2013 ; Jin et al, 2017 ; Yan et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

et al. 2021

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Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and has become a serious public health problem worldwide. Dipeptidyl peptidase-4 (DPP4) inhibitors, an emerging drug for the treatment of diabetes, have been found to have renoprotective effects in addition to glucose-lowering effects and therefore have the potential to be a treatment modality for DKD. Lobeliae Chinensis Herba (LCH), a traditional Chinese herb widely used in the treatment of diabetes, has recently been found to have a hypoglycaemic mechanism related to the inhibition of DPP4. Firstly, analysis of single-cell sequencing data from mouse kidneys in the National Center for Biotechnology Information (NCBI) database revealed that DPP4 was specifically upregulated in DKD podocytes and was associated with podocyte proliferation. Subsequently, the network pharmacology approach was applied to the screening of compounds. Twelve LCH active ingredients targeting DPP4 were extracted from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. In addition, these 12 compounds and DPP4 were molecularly docked to predict the probability of them affecting DPP4 activity. In vitro, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin were demonstrated to retard podocyte proliferation by inhibiting DPP4 activity and were the top five compounds predicted by molecular docking to be the most likely to affect DPP4 activity. The half maximal inhibitory concentration (IC50) of the five compounds for DPP4 activity were as follows. Acacetin Log IC50 = −8.349, 95%CI (−9.266, −7.265), Diosmtrin Log IC50 = −8.419, 95%CI (−8.889, −7.950), Log IC50 = −8.349, 95%CI (−9.266, −7.265), Methyl rosmarinate Log IC50 = −8.415, 95%CI (−8.751, −8.085), Kaempferol Log IC50 = −8.297, 95%CI (−9.001, −7.615), Quercetin Log IC50 = −8.864, 95%CI (−9.107, −8.615). Finally, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin qualified for pharmacokinetic and drug similarity screening and have the potential to be the most promising oral agents for the treatment of DKD.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

et al. 2021

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“…They can inhibit the farnesylation of many proteins including Ras to exert the antitumor effect [1]. Several FTIs are under investigation or development, of which R115777 (Zarnestra, Tipifarnib) has received more attention [19][20][21]. A few FTIs including R115777 have entered clinical study (phases I-III) with certain positive results in the treatment of leukemia and breast cancer, and some of them are used in combination with other therapeutic agents [22][23][24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

A farnesyl transferase inhibitor induces apoptosis of insulinoma pancreatic β cells of mouse

Gao¹,

Fu²,

Liu³

et al. 2018

biomedicalresearch

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This study is to investigate the effect of a Farnesyl Transferase Inhibitor (FTI) R115777 on apoptosis of mouse insulinoma pancreatic β cells. MTT assay was used to investigate the proliferative inhibition of in vitro cultured mouse insulinoma pancreatic β cell lines by a FTI R115777. The morphological changes of the cells were observed using a fluorescence microscope by staining with Hoechst 33258 and propidium iodide after the treatment with FTI R115777. The apoptosis rate of R115777-treated beta-TC-6 cells was detected by flow cytometry. The expressions of caspase-3 and caspase-9 of the R115777-treated beta-TC-6 cells were assayed by spectrophotometry. In addition, the sub-cellular distribution of cytochrome c and the expressions of Bax and Bcl-2 proteins were detected by Western blot. After the treatment with FTI R115777, the proliferation of the mouse insulinoma pancreatic β cell lines was significantly inhibited. Significant apoptosis was observed in the treated beta-TC-6 cells. The effect of R115777 on the apoptosis of beta-TC-6 cells showed time-and dose-dependent manners. The expressions of caspase-3, caspase-9 and Bax in the R115777-treated beta-TC-6 cells increased, while the expression of Bcl-2 decreased. The sub-cellular distribution of cytochrome-c changed, with reduced cytochrome-c in mitochondria and increased cytochrome-c in cytoplasm. FTI R115777 can inhibit the proliferation of mouse insulinoma pancreatic β cell lines, and might induce cell apoptosis through the mitochondrionmediated pathway. R115777 could be further studied as a potential antitumor drug.

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Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway

Kim

Cho

Jeong

et al. 2020

J cachexia sarcopenia muscle

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Background Muscle wasting, resulting from aging or pathological conditions, leads to reduced quality of life, increased morbidity, and increased mortality. Much research effort has been focused on the development of exercise mimetics to prevent muscle atrophy and weakness. In this study, we identified indoprofen from a screen for peroxisome proliferator‐activated receptor γ coactivator α (PGC‐1α) inducers and report its potential as a drug for muscle wasting. Methods The effects of indoprofen treatment on dexamethasone‐induced atrophy in mice and in 3‐phosphoinositide‐dependent protein kinase‐1 (PDK1)‐deleted C2C12 myotubes were evaluated by immunoblotting to determine the expression levels of myosin heavy chain and anabolic‐related and oxidative metabolism‐related proteins. Young, old, and disuse‐induced muscle atrophic mice were administered indoprofen (2 mg/kg body weight) by gavage. Body weight, muscle weight, grip strength, isometric force, and muscle histology were assessed. The expression levels of muscle mass‐related and function‐related proteins were analysed by immunoblotting or immunostaining. Results In young (3‐month‐old) and aged (22‐month‐old) mice, indoprofen treatment activated oxidative metabolism‐related enzymes and led to increased muscle mass. Mechanistic analysis using animal models and muscle cells revealed that indoprofen treatment induced the sequential activation of AKT/p70S6 kinase (S6K) and AMP‐activated protein kinase (AMPK), which in turn can augment protein synthesis and PGC‐1α induction, respectively. Structural prediction analysis identified PDK1 as a target of indoprofen and, indeed, short‐term treatment with indoprofen activated the PDK1/AKT/S6K pathway in muscle cells. Consistent with this finding, PDK1 inhibition abrogated indoprofen‐induced AKT/S6K activation and hypertrophic response. Conclusions Our findings demonstrate the effects of indoprofen in boosting skeletal muscle mass through the sequential activation of PDK1/AKT/S6K and AMPK/PGC‐1α. Taken together, our results suggest that indoprofen represents a potential drug to prevent muscle wasting and weakness related to aging or muscle diseases.

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The discovery of a novel compound with potent antitumor activity: virtual screening, synthesis, biological evaluation and preliminary mechanism study

Cited by 11 publications

References 29 publications

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

A farnesyl transferase inhibitor induces apoptosis of insulinoma pancreatic β cells of mouse

Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway

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