The new opportunities in medicinal chemistry of fourth-generation EGFR inhibitors to overcome C797S mutation

He, Jie; Zhou, Zhenhua; Sun, Xin; Yang, Zunhua; Zheng, Pengwu; Xu, Shan; Zhu, Wufu

doi:10.1016/j.ejmech.2020.112995

Cited by 52 publications

(35 citation statements)

References 57 publications

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“…Column chromatography was performed silica gel 300-400 mesh. 1 H NMR and 13 C NMR spectroscopic data were recorded with Bruker 400 MHz NMR spectrometer and JEOL-ECX 500 NMR spectrometer in DMSO-d6 solution, with TMS serving as the internal standard. The high-resolution mass spectrometer (HRMS) was tested in TSQ 8000 and AB SCIEX X500R QTOF.…”

Section: Methodsmentioning

confidence: 99%

“…And also it is an important target for new anti-cancer drug research. [1][2][3][4] As shown in Figure 1, lots of EGFR inhibitors such as Gefitinib, Erlotinib, and Lapatinib have been approved in market, which significantly improve the clinical treatment of cancer patients. 5 However, the resistance problems of EGFR inhibitors in clinic have been made it urgent to find novel generation of EGFR kinase inhibitors.…”

mentioning

confidence: 99%

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Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Yan¹,

Liu²,

Wang³

et al. 2022

HETEROCYCLES

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In this paper, we reported a new series of 5-trifluoromethylpyrimidine derivatives (4a-4f, 6a-6j) for cancer therapy. They were tested for antitumor activity in vitro on four human cancer cell lines including A549, K562, HepG2, MCF-7 and two kinase including wild type epidermal growth factor receptor tyrosine kinase (EGFR wt -TK) and c-Src. The results suggested that some of the compounds (4a, 4b, 4c, 4e, 6b, 6d, 6e, 6f, 6g, 6h) performed well activities. Especially 2-((2-((4-((2-(Cyclohexylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (6g) showed high antitumor activities against four cancer cell lines with 1.08 μM, 2.06 μM, 1.24 μM and 2.57 μM, respectively. Furthermore, compound 6g inhibited EGFR wt and Src at the values of 0.75 μM and 0.15 μM.Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which plays an important role in regulating cell growth, proliferation and differentiation and other physiological activities of cancer cells. And also it is an important target for new anti-cancer drug research. [1][2][3][4] As shown in Figure 1, lots of EGFR inhibitors such as Gefitinib, Erlotinib, and Lapatinib have been approved in market, which significantly improve the clinical treatment of cancer patients. 5 However, the resistance problems of EGFR inhibitors in clinic have been made it urgent to find novel generation of EGFR kinase inhibitors. 6,7

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Yan¹,

Liu²,

Wang³

et al. 2022

HETEROCYCLES

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“…After years of innovative research, several promising drug candidates have been evaluated in pre-clinical stages and phase I studies. 28 , 165 , 166 , 167 , 168 , 169 …”

Section: Exploration Of Next-generation Egfr-tkismentioning

confidence: 99%

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Yang

et al. 2021

The Innovation

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Summary The discovery that mutations in the EGFR gene are detected in up to 50% of lung adenocarcinoma patients, along with the development of highly efficacious epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of this frequently occurring lung malignancy. Indeed, the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy. Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). The first-generation TKIs include erlotinib, gefitinib, lapatinib, and icotinib; the second-generation ErbB family blockers include afatinib, neratinib, and dacomitinib; whereas osimertinib, approved by the FDA on 2015, is a third-generation TKI targeting EGFR harboring specific mutations. Compared with the first- and second-generation TKIs, third-generation EGFR inhibitors display a significant advantage in terms of patient survival. For example, the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months. Unfortunately, however, like other targeted therapies, new EGFR mutations, as well as additional drug-resistance mechanisms emerge rapidly after treatment, posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance. In this review, we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance. We also discuss the current status of fourth-generation EGFR inhibitors, which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.

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“…For example, the Food and Drug Administration (FDA) approved some compounds designed to delay metastatic prostate cancer [51]. In NSCLC, tyrosine kinase inhibitor, immune checkpoint inhibitors, and antibodies against interleukin 6 receptor (IL-6R) have shown antimetastatic effects [52][53][54]. Nevertheless, NSCLC is associated with high heterogeneity; therefore, we recommend the application of multifunctional agents.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…For example, some androgen receptor inhibitors (e.g., apalutamide, enzalutamide, and darolutamide) can delay metastases in high-risk nonmetastatic castration-resistant prostate cancer [51]. In NSCLC, the application of TKIs or ICIs and antibodies against IL-6R can suppress metastasis formation [52][53][54]. Nevertheless, NSCLC displays high heterogeneity, and multifunctional agents have a better chance of avoiding the development of resistance.…”

Section: Future Directionsmentioning

confidence: 99%

Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design

et al. 2021

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Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial–mesenchymal transition, and migration of cancer cells).

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The new opportunities in medicinal chemistry of fourth-generation EGFR inhibitors to overcome C797S mutation

Cited by 52 publications

References 57 publications

Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design

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