Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045

Zhao, Peng; Yao, Ming-Yu; Zhu, Sujie; Chen, Jiyun; Yun, Cai‐Hong

doi:10.1016/j.bbrc.2018.05.154

Cited by 58 publications

(45 citation statements)

References 29 publications

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“…Even though the platinum-complexes are categorized under, the first-line therapy majority of the patients receiving the chemotherapy showed platinum resistance [17]. [46,47] Docetaxel is an anti-mitotic chemotherapeutic agent, used mainly for the treatment of ovarian, breast cancer, and NSCLC. Docetaxel reversibly binds to tubulin with high affinity in a 1:1 stoichiometric ratio.…”

Section: Combination Chemotherapymentioning

confidence: 99%

“…Jia et al [46] and Zhao et al [47] identified two compounds individually (EAI045 and EAI001), showed the potential to overcome the resistance. These novel compounds were synthesized by screening over 2.5 million compound library to see allosteric site interaction property.…”

Section: Fourth-generation Agent Targeting Egfr and Their Structuresmentioning

confidence: 99%

“…Both the compounds were analyzed for its sensitivity against 250 types of protein kinase. It was found that these compounds are only sensitive to EGFR [46,47] (the relevant details are given in Table 1).…”

Section: Fourth-generation Agent Targeting Egfr and Their Structuresmentioning

confidence: 99%

“…The whole protein entity is composed of 331 amino acids, ranging from residue 695 to 1022 [46]. EAI001 has only one chain (A) of which 28% is composed of the helix, and 14% is the β-plated sheet, which comprises 355 amino acids ranging from residue 675 to 1022 [47]. EAI001 has one inhibitory residue, namely 9LLA 1101 [42].…”

Section: Secondary Structure Assessment Of Egfr Eai045 and Eai001mentioning

confidence: 99%

“…The figure states the residue sequence of both the compound along with this interaction site with the protein in the allosteric site of EGFR. These interaction sites are the main target for the inhibitors to bind along with the protein and can be a potential target for the identification of new moieties against EGFR mutation [47,48].…”

Section: Secondary Structure Assessment Of Egfr Eai045 and Eai001mentioning

confidence: 99%

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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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Section: Combination Chemotherapymentioning

confidence: 99%

Section: Fourth-generation Agent Targeting Egfr and Their Structuresmentioning

confidence: 99%

Section: Fourth-generation Agent Targeting Egfr and Their Structuresmentioning

confidence: 99%

Section: Secondary Structure Assessment Of Egfr Eai045 and Eai001mentioning

confidence: 99%

Section: Secondary Structure Assessment Of Egfr Eai045 and Eai001mentioning

confidence: 99%

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

2020

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A Perspective Study on the RTK, PI3K, B‐Raf, CDK and the Multi‐Protein Targeting in Medicinal Chemistry

Mohamed

Kerdawy

2022

Chemistry & Biodiversity

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The cellular signaling pathway components that control the different stages of cell maturation such as RTK, PI3K, B-Raf, and CDK represent crucial antitumor drug targets. The isoform diversity of these components revealed multi-divergent vents for cancer cells to develop several resistance mechanisms against these new selective drug targets. This review article illustrates the complex nature of cancer, moreover, molecular tracing of tumor resistance towards certain signaling pathways was presented. Several crucial interventions in this regard for antitumor agents' development were pointed out. The antitumor activities of several cancer chemotherapies targeting kinases were also discussed with a special focus on the structural bases for the design of protein kinase inhibitors. Additionally, a focused literature survey about the various targeted multi-kinase inhibition approaches as a mean to overcome cancer resistance was also included.

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Orthoallosteric EGFR‐TKIs: A New Paradigm in NSCLC Treatment Strategy Targeting the C797S Mutation

Ahmad,

Patel

2024

Drug Development Research

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The remarkable clinical success of third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) has significantly advanced the treatment landscape for non‐small‐cell lung cancer (NSCLC). However, the emergence of the tertiary point mutation C797S poses a substantial obstacle to their clinical efficacy, leading to a dearth of FDA‐approved targeted therapies for patients harboring this mutation. Addressing this pressing clinical challenge necessitates the development of novel therapeutic agents targeting the clinically challenging EGFR mutation. This review delves into the design strategies, antitumor activity, and crucial protein–drug interactions of recently introduced Orthoallosteric fourth‐generation EGFR‐TKIs. These inhibitors are distinguished by their ability to simultaneously engage both the canonical orthosteric (ATP) binding site and the allosteric site. By shedding light on these key aspects, the review serves as a valuable resource for medicinal chemists, empowering them to propel the advancement of fourth‐generation EGFR inhibitors.

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Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045

Cited by 58 publications

References 29 publications

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

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

A Perspective Study on the RTK, PI3K, B‐Raf, CDK and the Multi‐Protein Targeting in Medicinal Chemistry

Orthoallosteric EGFR‐TKIs: A New Paradigm in NSCLC Treatment Strategy Targeting the C797S Mutation

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