A Third Shot at EGFR: New Opportunities in Cancer Therapy

Guardiola, Salvador; Varese, Monica; Sánchez‐Navarro, Macarena; Giralt, Ernest

doi:10.1016/j.tips.2019.10.004

Cited by 78 publications

(62 citation statements)

References 119 publications

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“…Whether it is a sign of TKI development slow down or a natural development, ‘precision medicine’ has become an important step for management of the disease by stratification of patient cohorts into optimized treatment regimens according to molecular, pathophysiological and ‘omics profiling [20] . In addition to conventional therapies targeting EGFR, such as TKIs (provisionally via ligand-based drug design) and monoclonal antibodies (e.g., cetuximab, panitumumab, and necitumumab); a third strategy is now targeting EGF directly via EGFR-derived peptide-based inhibitors, anti-EGF vaccines, and single-domain antibodies (nanobodies) [21] .…”

Section: Egfr Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

Haddad

Remeš

Adam

et al. 2021

Drug Discovery Today

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Highlights Structural variations in EGFR should not be ignored in structure-based drug design. Main variations involve inward and outward folding of C-helix in the kinase N-lobe. Origins of variations are mutations and drug R-groups but not the drug core. Comparative modeling, fitting and clustering are imperative steps in EGFR drug design. Alternatively, volume and shape of binding site can be used to filter ligands against structures.

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Section: Egfr Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

Haddad

Remeš

Adam

et al. 2021

Drug Discovery Today

View full text Add to dashboard Cite

show abstract

“…These receptors are widely distributed in mammalian epithelial cell membranes and normally modulate different processes such as cell proliferation, death, and differentiation. It has been detected that an anomalous over-expression of these proteins has an important role in the formation and development of many types of solid tumours, principally Non-Small Cell Lung (NSCLC), breast, colorectal, head, and neck cancers types [ 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized.

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“…The EGFR secondary mutation or T790M mutation is the major reason for the resistance development in the first and second-generation drugs [27]. Osimertinib and rociletinib are pyrimidines classified under third-generation anti-EGRF drugs.…”

Section: Third-generation Egfr Drugsmentioning

confidence: 99%

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

2020

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Background The epidermal growth factor receptor (EGFR) inhibitors represent the first-line therapy regimen for non-small cell lung cancer (NSCLC). Most of these inhibitors target the ATP-site to stop the aggressive development of NSCLC. Stabilization of the ATP-binding on EGFR is difficult due to autophosphorylation of the EGFR domain. This leads to activation of nonintrinsic influence of the tumor microenvironment and expression of anti-apoptotic pathways and drug resistance. Methods The NSCLC related literature search was carried out using online databases such as Scopus, Web of Sciences, PubMed, Protein Data Bank and UniPort for the last ten years and selected articles are referred for discussion in this review. Results To overcome the problem of mutations in NSCLC, the allosteric site of EGFR was targeted, which shows significant therapeutic outcome without causing resistance. Compounds like EAI001, EAI045 JBJ-04-125-02, DDC4002 and a series of small molecules with an affinity towards the EGFR allosteric site are reported and are under the investigational stage. These compounds are categorized under fourth-generation anti-NSCLC agents. Conclusion Composition of this review highlights the advantage of inhibiting allosteric site in the EGFRTK receptor domains and presents a comparative analysis of the new fourth-generation anti-NSCLC agents to overcome the drug resistance.

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A Third Shot at EGFR: New Opportunities in Cancer Therapy

Cited by 78 publications

References 119 publications

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

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