Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC)

Pawara, Rahul; Ahmad, Iqrar; Nayak, Deepika; Wagh, Shivani; Wadkar, Avinash; Ansari, Azim; Belamkar, Sateesh; Surana, Sanjay J.; Kundu, Chanakya Nath; Patil, Chandragouda R.; Patel, Harun

doi:10.1016/j.bioorg.2021.105234

Cited by 47 publications

(26 citation statements)

References 63 publications

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“…The EGFR small-molecule tyrosine kinase inhibitors (TKIs) emerge as a promising inhibitory approach targeting EGFR. AG1478 is one of the EGFR-TKIs ( Zhang et al, 2008 ), which targets the adenosine triphosphate binding site on the intracellular kinase domain and prevents tyrosin kinase activation to inhibit EGFR ( Pawara et al, 2021 ). In this experiment, AG1478 was used to examine the relationship between EGFR signaling pathways and quercetin-rescued podocyte apoptosis through detecting the expression of apoptosis-related proteins by co-cultured of AG1478 and quercetin.…”

Section: Discussionmentioning

confidence: 99%

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Liu

et al. 2022

Front. Pharmacol.

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Podocytes injury is one of the leading causes of proteinuria in patients with diabetic nephropathy (DN), and is accompanied by podocytes apoptosis and the reduction of podocyte markers such as synaptopodin and nephrin. Therefore, attenuation of podocyte apoptosis is considered as an effective strategy to prevent the proteinuria in DN. In this study, we evaluated the anti-podocyte-apoptosis effect of quercetin which is a flavonol compound possessing an important role in prevention and treatment of DN and verified the effect by using db/db mice and high glucose (HG)-induced mouse podocytes (MPs). The results show that administration of quercetin attenuated the level of podocyte apoptosis by decreasing the expression of pro-apoptotic protein Bax, cleaved caspase 3 and increasing the expression of anti-apoptotic protein Bcl-2 in the db/db mice and HG-induced MPs. Furthermore, epidermal growth factor receptor (EGFR) was predicted to be the potential physiological target of quercetin by network pharmacology. In vitro and vivo experiments confirmed that quercetin inhibited activation of the EGFR signaling pathway by decreasing phosphorylation of EGFR and ERK1/2. Taken together, this study demonstrates that quercetin attenuated podocyte apoptosis through inhibiting EGFR signaling pathway, which provided a novel approach for further research of the mechanism of quercetin in the treatment of DN.

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Section: Discussionmentioning

confidence: 99%

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Liu

et al. 2022

Front. Pharmacol.

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“…A slight fluctuation of the residues in the active site and main chain fluctuated indicated that the conformational change was minimal, implying that the reported lead compound was firmly bound within the cavity of the target protein binding pocket. 38 For 100 ns, the MD simulation of the compound 27 –InhA complex was monitored and analyzed. As seen in Figure 12 B, it is clear that there were no significant fluctuations in amino acid residues after the binding of compound 27 to the active site.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Molecular Modeling Study, and Quantum-Chemical-Based Investigations of Isoindoline-1,3-diones as Antimycobacterial Agents

et al. 2022

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The condensation of phthalic anhydride afforded structurally modified isoindoline-1,3-dione derivatives with selected amino-containing compounds. The title compounds ( 2 – 30 ) have been characterized by thin-layer chromatography (TLC), infrared spectroscopy, 1 H and 13 C NMR spectroscopy, and mass spectroscopy. All of the compounds were assessed for their antimycobacterial activity toward the H37Rv strain by a dual read-out assay method. Among the synthesized compounds, compound 27 possessed a significant IC 50 of 18 μM, making it the most potent compound of the series. The InhA inhibitory (IC 50 ) activity of compound 27 was 8.65 μM in comparison to Triclosan (1.32 μM). Computational studies like density functional theory (DFT) study, molecular docking, and dynamic simulation studies illustrated the reactivity and stability of the synthesized compounds as InhA inhibitors. A quantum-mechanics-based DFT study was carried out to investigate the molecular and electronic properties, reactivities, and nature of bonding present in the synthesized compounds and theoretical vibrational (IR) and isotropic value ( 1 H and 13 C NMR) calculations.

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“…Unfortunately, overexpression of the EGFR gene initiates diverse downstream signaling pathways, resulting in cancer aggressiveness and invasiveness [ 2 ]. Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related mortality and morbidity globally, accounting for about 80–90% of all lung malignancies [ 2 , 3 , 4 , 5 ]. EGFR overexpression and mutation (L858R and T790M) is highly prevalent in NSCLC [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…The approved first-generation EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib ( Figure 1 ), provided significant clinical benefits in patients with activating mutations, resulting in marked tumor shrinkage [ 9 , 10 , 11 ]. However, acquired drug resistance usually develops after approximately a year of gefitinib or erlotinib treatment [ 4 ]. According to reports, around 60% of EGFR-mutant NSCLC patients have the EGFR T790M mutation, which renders first-generation EGFR inhibitors less effective in these patients [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…Drastically, the T790M mutation boosts the affinity of the EGFR receptor for ATP, leading to a lowering of the ability of EGFR inhibitors to compete with ATP effectively [ 12 ]. In the T790M mutation, a secondary Thr790 to Met790 mutation occurs in the gatekeeper site of the EGFR catalytic domain, whereas the L858R mutation is a single-nucleotide substitution that replaces leucine with arginine at position 858 [ 3 , 4 ]. In the case of the latter mutation, the EGFR receptor shows a 50-fold of raised catalytic activity, symbolizing a vital hub for cancer cells in rising cell growth, downstream signaling, and metastasis [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of New Hydantoin Acetanilide Derivatives as Anti-NSCLC Targeting EGFRL858R/T790M Mutations

et al. 2022

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Epidermal Growth Factor Receptor (EGFR), its wild type and mutations L858R/T790M, is overexpressed in non-small cell lung cancer (NSCLC) patients and is considered an inevitable oncology target. However, while the potential EGFR inhibitors have been represented in the literature, their cellular activity failed to establish broad potency against EGFR and its mutations. This study identifies a new series of EGFRL858R/T790M inhibitors bearing hydantoin acetanilides. Most compounds revealed strong antiproliferative activity in a range of NSCL cancer models (A549, H1975, and PC9), in which 5a and 5f were the most potent. Compounds 5a and 5f possessed potent anticancer activity on H1975 cells with IC50 values of 1.94 and 1.38 µM, respectively, compared to 9.70 µM for erlotinib. Favorably, 5a and 5f showed low activity on WI-38 normal cells. Western blotting and an EGFR kinase assay test proved the significant EGFR inhibitory activity of 5a. Besides, active hydantoin derivative 5a strongly arrested the cell cycle at the sub G1 and S phases and triggered apoptosis in A549 cells. These results imply that 5a could be considered a promising lead compound for additional development as a potential active agent for anticancer therapy.

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Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC)

Cited by 47 publications

References 63 publications

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

Synthesis, Molecular Modeling Study, and Quantum-Chemical-Based Investigations of Isoindoline-1,3-diones as Antimycobacterial Agents

Design and Synthesis of New Hydantoin Acetanilide Derivatives as Anti-NSCLC Targeting EGFRL858R/T790M Mutations

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