Novel 4-anilinoquinazoline derivatives featuring an 1-adamantyl moiety as potent EGFR inhibitors with enhanced activity against NSCLC cell lines

Yu, Haiqing; Li, Yanxia; Yang, Ge; Song, Zhendong; Wang, Changyuan; Huang, Shanshan; Jin, Yue; Han, Xu; Zhen, Yuhong; Liu, Kexin; Zhou, Youwen; Ma, Xiaodong

doi:10.1016/j.ejmech.2016.01.045

Cited by 28 publications

(13 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Quinazoline derivative is the group of compounds that have been widely used as EGFR inhibitor [6], such as erlotinib [7], gefitinib [8], afatinib [9], and WZ4002 [10]. Erlotinib and gefitinib are classified as the first-generation EGFR inhibitor.…”

Section: ■ Introductionmentioning

confidence: 99%

Design of New Quinazoline Derivative as EGFR (Epidermal Growth Factor Receptor) Inhibitor through Molecular Docking and Dynamics Simulation

2020

View full text Add to dashboard Cite

Erlotinib, Afatinib, and WZ4002 are quinazoline derivative compounds and classified as first, second, and third-generation EGFR inhibitor. All inhibitors have been given directly to cancer patients for many years but find some resistance. These three compounds are candidates as the lead compound in designing a new inhibitor. This work aims to design a new potential quinazoline derivative as an EGFR inhibitor focused on the molecular docking result of the lead compound. The research method was started in building a pharmacophore model of the lead compound then used to design a new potential inhibitor by employing the AutoDock 4.2 program. Molecular dynamics simulation evaluates the interaction of all complexes using the Amber15 program. There are three new potential compounds (A1, B1, and C1) whose hydrogen bond interaction in the main catalytic area (Met769 residue). The Molecular Mechanics Generalized Born Surface Area (MM-GBSA) binding energy calculation shows that B1 and C1 compounds have lower binding energies than erlotinib as a positive control, which indicates that B1 and C1 are potential as EGFR inhibitor.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Design of New Quinazoline Derivative as EGFR (Epidermal Growth Factor Receptor) Inhibitor through Molecular Docking and Dynamics Simulation

2020

View full text Add to dashboard Cite

show abstract

“…Unfortunately, only osimertinib possesses exceptional biological properties, and has thus been approved in 2015 for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC [16]. On the basis of considerable efforts to identify more effective and safe agents to overcome gefitinib-produced resistances [17][18][19], we found the novel diphenylpyrimidine derivative N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (6, DY3002, Figure 2) [20]. The molecule displayed enhanced activity and increased selectivity against EGFR T790M and was thus reported as a promising NSCLC clinical candidate.…”

Section: Introductionmentioning

confidence: 99%

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

Song

Jin

et al. 2016

Molecules

Self Cite

View full text Add to dashboard Cite

Abstract:Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates.However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFR T790M ) (IC 50 = 0.71 nM) over wild-type EGFR (IC 50 = 448.7 nM) in kinase assays. Compared to rociletinib (SI = 21.4) and osimertinib (SI = 40.9), it significantly increased selectivity (SI = 632.0) against EGFR T790M over wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC 50 value of 0.037 µM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFR T790M -mutated NSCLC.

show abstract

“…Both compounds 37 and 38 were found promising in EGFR kinase inhibition; further, development can help find more potent compounds (Table 1). Yu et al (2016) have synthesized some novel derivatives of 4-anilinoquinazoline bearing 1-adamantyl moiety. Most of the derivatives reported displayed potent EGFR kinase inhibitory activity with IC 50 value ≥10 nM.…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

An appraisal of anticancer activity with structure–activity relationship of quinazoline and quinazolinone analogues through EGFR and VEGFR inhibition: A review

Haider

Das

Joseph

et al. 2022

Drug Development Research

View full text Add to dashboard Cite

Cancer is one of the leading causes of death. Globally a huge number of deaths and new incidences are reported annually. Heterocyclic compounds have been proved to be very effective in the treatment of different types of cancer. Among different heterocyclic scaffolds, quinazoline and quinazolinone core were found versatile and interesting with many biological activities. In the discovery of novel anticancer agents, the Quinazoline core is very effective. The FDA has approved more than 20 drugs as an anticancer bearing quinazoline or quinazolinone core in the last two decades. One prime example is Dacomitinib, which was newly approved for non-small-cell lung carcinoma treatment in 2018. These drugs work by different pathways to prevent the spread of cancer cell progression, including inhibition of different kinases, tubulin, kinesin spindle protein, and so forth. This review presented recent developments of quinazoline/quinazolinone scaffold bearing derivatives as anticancer agents acting as epidermal growth factor receptor (EGFR) vascular endothelial growth factor receptor (VEGFR), and dual EGFR/VEGFR inhibitors.

show abstract

Novel 4-anilinoquinazoline derivatives featuring an 1-adamantyl moiety as potent EGFR inhibitors with enhanced activity against NSCLC cell lines

Cited by 28 publications

References 37 publications

Design of New Quinazoline Derivative as EGFR (Epidermal Growth Factor Receptor) Inhibitor through Molecular Docking and Dynamics Simulation

Design of New Quinazoline Derivative as EGFR (Epidermal Growth Factor Receptor) Inhibitor through Molecular Docking and Dynamics Simulation

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

An appraisal of anticancer activity with structure–activity relationship of quinazoline and quinazolinone analogues through EGFR and VEGFR inhibition: A review

Contact Info

Product

Resources

About