Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC

Chen, Lingfeng; Fu, Weitao; Chen, Feng; Qu, Rong; Tong, Linjiang; Zheng, Lulu; Fang, Bo; Qiu, Yinda; Hu, Jie; Cai, Yuepiao; Feng, Jiaxuan; Xie, Hua; Ding, Jian; Liu, Zhiguo; Liang, Guang

doi:10.1016/j.ejmech.2017.08.061

Cited by 18 publications

(9 citation statements)

References 38 publications

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“…Nowadays, drugs with polypharmacological activities are shown to be advantageous over combination therapy as their lower incidences of side effects and more resilient therapies (Anighoro et al, 2014). Thus, in the current study, we find that compound 15c, an EGFR L858R/T790M selective inhibitor in our previous study (Chen et al, 2017a), exhibited a dual inhibitory activity against EGFR L858R/T790M and FGFR1 and efficiently overcame the EGFR-TKI tolerance in EGFR-mutated NSCLC cells via concurrently inhibiting these two kinases activity. We suggest that 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.…”

Section: Introductionsupporting

confidence: 56%

“…In our previous work (Chen et al, 2017a), we designed and optimized a series analogue of WZ4002 and evaluated their inhibition activity against EGFR L858R/T790M , and found that several derivatives exhibited a high potency and selectivity between EGFR L858R/T790M and EGFR WT . In order to explore whether those compounds can inhibit the FGFR1 kinase activity, all the compounds were measured the kinase inhibitory effect against EGFR WT , EGFR L858R/T790M , and FGFR1 WT in a cell-free system called Caliper Mobility Shift Assay.…”

Section: Compound 15c Acted As An Egfr L858r/ T790m /Fgfr1 Dual Inhibmentioning

confidence: 99%

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Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers

Chen

Bao²,

Weng

et al. 2020

Front. Pharmacol.

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In the past decades, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved as an effective treatment strategy for the patients with EGFRmutated non-small-cell lung cancer (NSCLC). However, the tolerance for the EGFR-TKI always occurred after continuous administration for a period of time and limiting the application of these drugs. Activation of FGFR1 signaling pathway was one of the important escape mechanisms for EGFR-TKI resistant in NSCLC. Here, a novel dual inhibitor of EGFR L858R/T790M and FGFR1, compound15c, was found and can efficiently overcame the EGFR-TKI resistance via its simultaneous inhibition of their kinase activities. Comparison with EGFR L858R/T790M and FGFR1 inhibitor treatment alone or combined revealed that the inhibition of EGFR L858R/T790M and FGFR1 activity by 15c was responsible for surmounting the intrinsic EGFR-TKI resistance in EGFR L858R/T790M-mutated H1975 cells and the acquired resistance in Afatinib-tolerant PC9 cells (AFA-PC9). Flow Cytometry and Caspase3 activity analysis assay showed that 15c induced significant the early apoptosis of H1975 cells. Xenograft tumor formation in BALB/c mice induced by a H1975 cells was suppressed by 15c treatment, with no changes in animal body weight. Generally, 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.

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Section: Introductionsupporting

confidence: 56%

Section: Compound 15c Acted As An Egfr L858r/ T790m /Fgfr1 Dual Inhibmentioning

confidence: 99%

Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers

Chen

Bao²,

Weng

et al. 2020

Front. Pharmacol.

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“…Nucleophilic aromatic substitution (S N Ar) reactions are versatile transformations in the organic chemistry arsenal, and one of the important reactions used for making pharmacologically , and biologically active molecules. − The reaction mechanism of this transformation , involves a stepwise addition–elimination sequence, − wherein the first step involves a nucleophilic attack of the substrate to provide a Meisenheimer complex, followed by the loss of the leaving group through either catalyzed or noncatalyzed pathways. − The reaction typically involves an amine as the nucleophile, although a wide variety of non-nitrogenous nucleophiles may be used. This study reports HTE evaluation of S N Ar reactions performed in both droplets/thin film and bulk microtiter formats with analysis by DESI-MS. After HTE evaluation, validation of the reaction hotspots were performed in flow to increase confidence in the HTE findings (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions

et al. 2020

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Nucleophilic aromatic substitution (SNAr) reactions were optimized using high-throughput experimentation techniques for execution under flow conditions. A total of 3072 unique reactions were evaluated with an analysis time of ∼3.5 s per reaction using a system that combines a liquid handling robot for reaction mixture preparation with desorption electrospray ionization (DESI) mass spectrometry (MS) for analysis. The reactions were performed in bulk microtiter arrays with and without incubation. In-house developed software was used to process the data and generate heat maps of the results. This information was then used to select the most promising conditions for continuous synthesis under microfluidic reactor conditions. Our results show that this HTE approach provides robust guidance for narrowing the range of conditions needed for optimization of SNAr reactions.

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“…Both B5 and B6 compounds displayed marked TGI in a dose-dependent manner in H1975 xenograft mouse model, in vivo. In addition, B5 and B6 did not induce mortality, significant weight loss, or any toxicity and thus, these two compounds may be potential drug candidates for EGFR T790M mutant NSCLC (Chen et al, 2017).…”

Section: -Amino-pyrimidine Derivativesmentioning

confidence: 91%

Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in non‐small‐cell lung cancer: A comprehensive review

et al. 2022

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EGFR-positive non-small-cell lung cancer (NSCLC) due to primary mutation (EGFR DEL19 & L858R) has been recognized as a crucial mediator of tumor progression. This led to the development and approval of EGFR tyrosine kinase inhibitors, which addresses EGFR-mediated NSCLC but fail to show potency after initial months of therapy due to acquired resistance (EGFR T790M, EGFR C797S). Extensive research allowed identification of drugs for EGFR-positive NSCLC, wherein the majority of compounds have a pyrimidine substructure offering marked therapeutic benefits compared with chemotherapy. This current review outlines the diverse pyrimidine derivatives with amino-linked and fused pyrimidine scaffolds such as furo-pyrimidine, pyrimido-pyrimidine, thienopyrimidine, highlighting pyrimidine EGFR TK inhibitors reported in research emphasizing structural aspects, design approaches, inhibition potential, selectivity profile toward mutant EGFR conveyed through biological evaluation studies.Furthermore, mentioning the in-silico interaction profile of synthesized compounds for evaluating the binding affinity with key amino acids. The epilogue of review focuses on the recent research that drives forward to aid in the discovery and development of substituted amino and fused scaffolds of pyrimidine that can counteract the mutations and effectively manage EGFR-positive NSCLC.

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Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC

Cited by 18 publications

References 38 publications

Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers

Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers

High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions

Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in non‐small‐cell lung cancer: A comprehensive review

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