Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening

Elkamhawy, Ahmed; Ammar, Usama M.; Paik, Sora; Abdellattif, Magda H.; Elsherbeny, Mohamed H.; Lee, Kyeong; Roh, Eun Joo

doi:10.3390/molecules26175324

Cited by 11 publications

(14 citation statements)

References 45 publications

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“…The in vitro kinase inhibitory assay was performed at Reaction Biology Corp ( accessed on 15 February 2022) using Kinase HotSpotSM in order to measure the inhibitory activities of tested candidates, as previously performed [ 20 , 21 ]. The experiment contained specific kinase/substrate pairs along with required cofactors.…”

Section: Methodsmentioning

confidence: 99%

2-(3-Bromophenyl)-8-fluoroquinazoline-4-carboxylic Acid as a Novel and Selective Aurora A Kinase Inhibitory Lead with Apoptosis Properties: Design, Synthesis, In Vitro and In Silico Biological Evaluation

Elsherbeny

Ammar

Abdellattif

et al. 2022

Life

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New quinazoline derivatives were designed based on the structural modification of the reported inhibitors to enhance their selectivity toward Aurora A. The synthesized compounds were tested over Aurora A, and a cytotoxicity assay was performed over NCI cell lines to select the best candidate for further evaluation. Compound 6e (2-(3-bromophenyl)-8-fluoroquinazoline-4-carboxylic acid) was the most potent compound among the tested derivatives. A Kinase panel assay was conducted for compound 6e over 14 kinases to evaluate its selectivity profile. Further cell cycle and apoptosis analysis were evaluated for compound 6e over the MCF-7 cell line at its IC50 of 168.78 µM. It arrested the cell cycle at the G1 phase and induced apoptosis. Molecular docking was performed to explore the possible binding mode of compound 6e into the active site. It showed significant binding into the main pocket in addition to potential binding interactions with the key amino acid residues. Accordingly, compound 6e can be considered a potential lead for further structural and molecular optimization of the quinazoline-based carboxylic acid scaffold for Aurora A kinase selective inhibition with apoptosis properties.

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Section: Methodsmentioning

confidence: 99%

2-(3-Bromophenyl)-8-fluoroquinazoline-4-carboxylic Acid as a Novel and Selective Aurora A Kinase Inhibitory Lead with Apoptosis Properties: Design, Synthesis, In Vitro and In Silico Biological Evaluation

Elsherbeny

Ammar

Abdellattif

et al. 2022

Life

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“…The macrocycle zotiraciclib ( 57 ) shows spectrum-selective kinase inhibition of CDK9, Janus kinase 2 (JAK2), and FLT3 in the treatment of cancer. Moreover, CDK1/human epidermal growth factor receptor (HER2) dual-inhibitor indole-based derivatives exhibit potent inhibitory activities . A dual glycogen synthase kinase-3β (GSK-3β)/CDK inhibitor induces MM cell death and eliminates the putative cancer stem cell population.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, CDK1/human epidermal growth factor receptor (HER2) dual-inhibitor indole-based derivatives exhibit potent inhibitory activities. 201 A dual glycogen synthase kinase-3β (GSK-3β)/CDK inhibitor induces MM cell death and eliminates the putative cancer stem cell population. The dual CDK4/6 and pim-3 proto-oncogene (PIM3) inhibitor ETH-155008 fulfills the promise of effective B-cell lymphoma therapy.…”

Section: Discussionmentioning

confidence: 99%

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

et al. 2022

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Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure–activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.

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“…The dock scoring in MOE software was calculated using the London dG scoring function and refined using two different methods ( Table 7 ). The planarity of the system was maintained, and the best poses were analyzed for the best score ( Elkamhawy et al, 2021 ; Sait et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Novel saccharin analogs as promising antibacterial and anticancer agents: synthesis, DFT, POM analysis, molecular docking, molecular dynamic simulations, and cell-based assay

et al. 2022

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Saccharine is a pharmacologically significant active scaffold for various biological activities, including antibacterial and anticancer activities. Herein, saccharinyl hydrazide (1) was synthesized and converted into 2-[(2Z)-2-(1,1-dioxo-1,2-dihydro-3H-1λ6,2- benzothiazole-3-ylidene) hydrazinyl] acetohydrazide (5), which was employed as a key precursor for synthesizing a novel series of small molecules bearing different moieties of monosaccharides, aldehydes, and anhydrides. Potent biological activities were found against Staphylococcus and Escherichia coli, and the results indicated that compounds 6c and 10a were the most active analogs with an inhibition zone diameter of 30–35 mm. In cell-based anticancer assay over Ovcar-3 and M-14 cell lines, compound 10a was the most potent analog with IC50 values of 7.64 ± 0.01 and 8.66 ± 0.01 µM, respectively. The Petra Orisis Molinspiration (POM) theoretical method was used to calculate the drug score of tested compounds and compare them with their experimental screening data. Theoretical DFT calculations were carried out in a gas phase in a set of B3LYP 6-311G (d,p). Molecular docking studies utilizing the MOE indicated the best binding mode with the highest energy interaction within the binding sites. The molecular docking for Ovcar-3 was carried out on the ovarian cancer protein (3W2S), while the molecular docking for M-14 melanoma was carried out on the melanoma cancer protein (2OPZ). The MD performed about 2ns simulations to validate selected compounds’ theoretical studies.

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Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening

Cited by 11 publications

References 45 publications

2-(3-Bromophenyl)-8-fluoroquinazoline-4-carboxylic Acid as a Novel and Selective Aurora A Kinase Inhibitory Lead with Apoptosis Properties: Design, Synthesis, In Vitro and In Silico Biological Evaluation

2-(3-Bromophenyl)-8-fluoroquinazoline-4-carboxylic Acid as a Novel and Selective Aurora A Kinase Inhibitory Lead with Apoptosis Properties: Design, Synthesis, In Vitro and In Silico Biological Evaluation

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

Novel saccharin analogs as promising antibacterial and anticancer agents: synthesis, DFT, POM analysis, molecular docking, molecular dynamic simulations, and cell-based assay

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