Synthesis and Biological Evaluation of Pyrimidine-Based Dual Inhibitors of Human Epidermal Growth Factor Receptor 1 (HER-1) and HER-2 Tyrosine Kinases

Young, Mi; Lee, Kwang-Ok; Kang, Seok-Jong; Jung, Young Hee; Song, Ji Yeon; Choi, Kyung San; Byun, Joo Yun; Lee, Hanjae; Lee, Gwan Sun; Park, Seung Bum; Kim, Maeng Sup

doi:10.1021/jm201758g

Cited by 32 publications

(4 citation statements)

References 26 publications

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“…aCancer cells were purchased from Nanjing KeyGen Biotech Co. Ltd, and subcultured by State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University.bThe description was abstracted by the reference [27].cAntiproliferative activity was measured using the WST-1 assay. Values are the average of two independent experiments run in triplicate.…”

Section: Resultsmentioning

confidence: 99%

Optimization of Substituted 6-Salicyl-4-Anilinoquinazoline Derivatives as Dual EGFR/HER2 Tyrosine Kinase Inhibitors

Qin

Sun

et al. 2013

PLoS ONE

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4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6-salicyl-4-anilinoquinazoline derivatives 9–27 were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound 21 revealed the most potent dual EGFR/HER2 inhibitory activity, with IC50 values of 0.12 µM and 0.096 µM, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of 21 was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound 21 into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound 21 as a potent EGFR/HER2 dual kinase inhibitor.

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Section: Resultsmentioning

confidence: 99%

Optimization of Substituted 6-Salicyl-4-Anilinoquinazoline Derivatives as Dual EGFR/HER2 Tyrosine Kinase Inhibitors

Qin

Sun

et al. 2013

PLoS ONE

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“…We depict the ten most influential molecular structures or atoms for HER2-positive breast cancer MDA-MB-361 in Figure a. The HER-2 inhibitors synthesized by Cha et al (Figure b) further validate our findings, exhibiting MACCS 78, MACCS 134, PubChem 16, PubChem 489, PubChem 502, and PubChem 638 as key features. “?” in MACCS 48 represents atoms that are neither carbon nor hydrogen and “?” in PubChem 502 represents atoms that are carbon with the least hydrogen atom.…”

Section: Resultsmentioning

confidence: 99%

A New Fingerprint and Graph Hybrid Neural Network for Predicting Molecular Properties

Zhang,

Mao,

et al. 2024

J. Chem. Inf. Model.

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Machine learning plays a role in accelerating drug discovery, and the design of effective machine learning models is crucial for accurately predicting molecular properties. Characterizing molecules typically involves the use of molecular fingerprints and molecular graphs. These are input into a multilayer perceptron (MLP) and variants of graph neural networks, such as graph attention networks (GATs). Due to the diverse types and large dimension of fingerprints, models may contain many features that are relatively irrelevant or redundant; meanwhile, although the GAT excels in handling heterogeneous graph tasks, it lacks the ability to extract collaborative information from neighboring nodes, which is crucial in scenarios where it cannot capture the joint influence of adjacent groups on atoms. To overcome these challenges, we introduce a hybrid model, combining improved GAT and MLP. In GAT, the recurrent neural network is employed to capture collaborative information. To address the dimensionality issue, we propose a feature selection algorithm, which is based on the principle of maximizing relevance while minimizing redundancy. Through experiments on 13 public data sets and 14 breast cell lines, our model demonstrates superior performance compared to state-of-the-art deep learning and traditional machine learning algorithms. Additionally, a series of ablation experiments were conducted to demonstrate the advantages of our improved version, as well as its antinoise capability and interpretability. These results indicate that our model holds promising prospects for practical applications.

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“… 557 – 559 Lapatinib, a member of the quinazoline class, has a role as an antineoplastic agent and as a TK inhibitor. 560 Raymonda et al showed that lapatinib has the potential to block SARS-CoV-2 infection by a high-throughput screening procedure. 561 According to their in vitro results, lapatinib could inhibit SARS-CoV-2 RNA replication in pulmonary fibroblasts by over 50,000-fold.…”

Section: Structures Of Small Molecule Drugs For Covid-19 Therapymentioning

confidence: 99%

Small molecules in the treatment of COVID-19

Lei

Chen

Jin

et al. 2022

Sig Transduct Target Ther

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The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and Mpro, interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.

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Synthesis and Biological Evaluation of Pyrimidine-Based Dual Inhibitors of Human Epidermal Growth Factor Receptor 1 (HER-1) and HER-2 Tyrosine Kinases

Cited by 32 publications

References 26 publications

Optimization of Substituted 6-Salicyl-4-Anilinoquinazoline Derivatives as Dual EGFR/HER2 Tyrosine Kinase Inhibitors

Optimization of Substituted 6-Salicyl-4-Anilinoquinazoline Derivatives as Dual EGFR/HER2 Tyrosine Kinase Inhibitors

A New Fingerprint and Graph Hybrid Neural Network for Predicting Molecular Properties

Small molecules in the treatment of COVID-19

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