Novel third-generation pyrimidines-based EGFR tyrosine kinase inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer

An, Baijiao; Liu, Jian; Fan, Yangyang; Nie, Wenyan; Yang, Chunhua; Yao, Han; Li, Wei; Zhang, Yin; Li, Xingshu; Tian, Geng

doi:10.1016/j.bioorg.2022.105743

Cited by 10 publications

(4 citation statements)

References 30 publications

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“…For this, LO2 (human normal liver cells) and HK2 (human kidney proximal convoluted tubule epithelial cells), two different types of nontumorigenic cell lines, were used. 47 The results reported in Table 7 indicated that 13c exhibited a far safer impact on normal human cells (LO2 and HK2) with IC 50 values of 30.88 ± 0.98 and 53.39 ± 1.58 μM, respectively, using 5-FU as a positive control, which presented IC 50 values of 18.71 ± 0.48 and 34.01 ± 0.98 μM, respectively.…”

Section: Resultsmentioning

confidence: 94%

“…The comprehensive procedures of biological assays of the target sulphonamides series I ( 3a–c, 5a–d , and 7a–e ) and series II ( 9, 11a,b, 13a–e, and 15a,b ) are presented in the Supplementary materials , including; CA I, II, IX, and XII inhibition studies, 33 NCI-USA screening, 50 , 72 antiproliferative activities under hypoxic conditions, 73 toxicity towards normal human cells, 47 cell migration study, 48 colony formation assay, 49 apoptosis assay, 74 and cell cycle analysis. 75 , 76 …”

Section: Experimental Protocolsmentioning

confidence: 99%

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Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

Tawfik

Belal

Abourehab

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Herein we reported the design and synthesis of two series comprising twenty-two benzenesulfonamides that integrate the s -triazine moiety. Target compounds successfully suppressed the hCA IX, with IC 50 ranging from 28.6 to 871 nM. Compounds 5d , 11b , 5b , and 7b were the most active analogues, which inhibited hCA IX isoform in the low nanomolar range ( K I = 28.6, 31.9, 33.4, and 36.6 nM, respectively). Furthermore, they were assessed for their cytotoxic activity against a panel of 60 cancer cell lines following US-NCI protocol. According to five-dose assay, 13c showed significant anticancer activity than 5c with GI 50 -MID values of 25.08 and 189.01 µM, respectively. Additionally, 13c ’s effects on wound healing, cell cycle disruption, and apoptosis induction in NCI-H460 cancer cells were examined. Further, docking studies combined with molecular dynamic simulation showed a stable complex with high binding affinity of 5d to hCA IX, exploiting a favourable H-bond and lipophilic interactions. HIGHLIGHTS Carbonic anhydrase (CA) inhibitors comprising rigid and flexible linkers were developed. Compound 5d is the most potent CA IX inhibitor in the study (IC50: 28.6 nM). Compounds 5c and 13c displayed the greatest antiproliferative activity towards 60 cell lines. Compound 13c exposed constructive outcomes on normal cell lines, metastasis, and wound healing. Molecular docking and molecular dynamics (MDs) simulation was utilised to study binding mode.

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Section: Resultsmentioning

confidence: 94%

Section: Experimental Protocolsmentioning

confidence: 99%

Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

Tawfik

Belal

Abourehab

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The X-ray crystal structure of Osimertinib and mutant EGFR T790M has confirmed that the U-shaped configuration and the important interaction of pyrimidine core which formed two-dentate hydrogen bonds with the hinge residue Met793 [29,30] . Therefore, the scaffold of pyrimidine has been retained and fused with various electron-withdrawing or electron-donating groups (P2) to explore the interactions with EGFR.…”

Section: Introductionmentioning

confidence: 83%

Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing dihydroquinoxalinone as novel EGFRL858R/T790M kinase inhibitors against non-small-cell lung cancer

Chen

et al. 2022

Preprint

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The clinical responses to the EGFR kinase inhibitors in non-small cell lung cancer (NSCLC) patients are always followed by drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFRT790M are also limited by the toxicity due to the concurrent inhibition of wide-type (WT) EGFR. Here we employed splicing principle to design and synthesize a series of aminopyrimidine derivatives bearing dihydroquinoxalinone (8-15) as novel thirdgeneration inhibitors against double mutant L858R/T790M in EGFR. It’s worth noting that compound 10 presented remarkable inhibitory activity against EGFRL858R/T790M (IC50 = 15 ± 1.8 nM) and anti-proliferative effect against H1975 cells (IC50 = 166.43 ± 14.45 nM). Moreover, the obvious down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent efficacy. These results demonstrated that compound 10 deserves the further exploration.

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“…Additionally, 35 a was subjected for in vivo evaluation, and the results indicated that it inhibited the growth of tumours in an H1975 xenograft model (25 mg/kg/d, TGI: 90.24 %). [103] A series of urea-linked pyrimidine analogues were disclosed by Limin and colleagues to assess their anticancer potential. The antiproliferative tests on the designed scaffolds revealed that 36 a (Figure 40) was the most promising one, with an IC 50 value of 2.51 μM.…”

Section: Chemistryselectmentioning

confidence: 99%

Nitrogen‐Containing Heterocyclic Scaffolds as EGFR Inhibitors: Design Approaches, Molecular Docking, and Structure‐Activity Relationships

Pal¹,

Teli²,

Matada³

et al. 2023

ChemistrySelect

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proved to be the magical weapon in designed and discovery of synthetic molecules as they acquired comprehensive range of pharmacological properties. In recent year (2018-2022) Nheterocyclic derivatives were uncovered as the potential EGFR TKIs. The present review summarised the research progress of EGFR TKIs to dazed the limitations of currently accessible drugs by consecrating, anatomy, mutation of EGFR, and its role in different types of cancer. The review highlights the medicinal chemistry prospective emphasising about the designing strategies, docking studies, biological evaluation, selectivity and structural activity relationship of N-heterocyclic compounds. Our review will support the medicinal chemists in direction for the development of novel N-heterocyclic based EGFR TKIs.

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Novel third-generation pyrimidines-based EGFR tyrosine kinase inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer

Cited by 10 publications

References 30 publications

Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing dihydroquinoxalinone as novel EGFRL858R/T790M kinase inhibitors against non-small-cell lung cancer

Nitrogen‐Containing Heterocyclic Scaffolds as EGFR Inhibitors: Design Approaches, Molecular Docking, and Structure‐Activity Relationships

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