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

ABSTRACT: Most of the available crystal structures of epidermal growth factor receptor (EGFR) kinase domain, bound to drug inhibitors, originated from ligand-based drug design studies. Here, we used variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. The families shared similar mutational profiles and similarity in the ligand R-groups (chemical composition, geometry, and charge) facing the C-helix, mutation sites, and DFG domain. For structure-based drug design, we recommend a systematic decision-making process for choice of template, guided by appropriate pairwise fitting and clustering before the molecular docking step. Alternatively, the binding site shape/volume can be used to filter and select the compound libraries.

SUBMITTER: Haddad Y

PROVIDER: S-EPMC7567673 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Structure-Based Drug Design Studies Toward the Discovery of Novel Chalcone Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors.

Project description:Human Epidermal Growth Factor Receptor-1 (EGFR), a transmembrane tyrosine kinase receptor (RTK), has been associated with several types of cancer, including breast, lung, ovarian, and anal cancers. Thus, the receptor was targeted by a variety of therapeutic approaches for cancer treatments. A series of chalcone derivatives are among the most highly potent and selective inhibitors of EGFR described to date. A series of chalcone derivatives were proposed in this study to investigate the intermolecular interactions in the active site utilizing molecular docking and molecular dynamics simulations. After a careful analysis of docking results, compounds 1a and 1d were chosen for molecular dynamics simulation study. Extensive hydrogen bond analysis throughout 7 ns molecular dynamics simulation revealed the ability of compounds 1a and 1d to retain the essential interactions needed for the inhibition, especially MET 93. Finally, MM-GBSA calculations highlight on the capability of the ligands to bind strongly within the active site with binding energies of -44.04 and -56.6 kcal/mol for compounds 1a and 1d, respectively. Compound 1d showed to have a close binding energy with TAK-285 (-66.17 kcal/mol), which indicates a high chance for compound 1d to exhibit inhibitory activity, thus recommending to synthesis it to test its biological activity. It is anticipated that the findings reported here may provide very useful information for designing effective drugs for the treatment of EGFR-related cancer disease.

| S-EPMC6321200 | biostudies-literature

Epidermal Growth Factor Receptor (EGFR) Antagonist Chimeric Anti-EGFR Monoclonal Antibody Trial

Project description:The study is an double blind, randomized, multicenter phase 3 trial. The efficacy analyses are based on 570 Chinese patients with RAS wt mCRC treated with mFOLFOX-6 ± cetuximab. Study treatment continues until disease progression or unacceptable toxicity (ie, not for a fixed number of courses). The primary endpoint of the study is progression-free survival (PFS) time according to RECIST 1.0; key secondary endpoints include overall survival (OS) time, overall response rate (ORR), and safety/tolerability.

| 2265349 | ecrin-mdr-crc

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR).

Project description:Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are two extensively studied membrane-bound receptor tyrosine kinase proteins that are frequently overexpressed in many cancers. As a result, these receptor families constitute attractive targets for imaging and therapeutic applications in the detection and treatment of cancer. This review explores the dynamic structure and structure-function relationships of these two growth factor receptors and their significance as it relates to theranostics of cancer, followed by some of the common inhibition modalities frequently employed to target EGFR and VEGFR, such as tyrosine kinase inhibitors (TKIs), antibodies, nanobodies, and peptides. A summary of the recent advances in molecular imaging techniques, including positron emission tomography (PET), single-photon emission computerized tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and optical imaging (OI), and in particular, near-IR fluorescence imaging using tetrapyrrolic-based fluorophores, concludes this review.

| S-EPMC7922143 | biostudies-literature

Targeting Epidermal Growth Factor Receptor (EGFR) in Pediatric Colorectal Cancer.

Project description:Background: Colorectal carcinoma (CRC) is very rare in the pediatric and adolescent age range and clinical management is performed according to adult protocols. We report, for the first time in the literature, a case of a child with metastatic CRC successfully treated with panitumumab associated to chemotherapy. Methods: A twelve-year-old male was diagnosed with CRC with nodal metastasis and peritoneal neoplastic effusion. After performing a genetic evaluation, in light of the absence of mutations in RAS family genes, anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody, panitumumab, was added to chemotherapy FOLFOXIRI. Results: The child successfully responded to therapy with normalization of the Carbohydrate Antigen (CA) 19.9 value after the third cycle of treatment. After the sixth cycle, he underwent surgery that consisted in sigmoid resection with complete D3 lymphadenectomy. At histological evaluation, no residual neoplastic cells were detectable in the surgical specimen. He completed 12 cycles of chemotherapy plus panitumomab and he is alive without disease 14 months from diagnosis. Conclusions: Our results suggest performing mutational screening for colorectal cancer also in the pediatric setting, in order to orient treatment that should include targeted therapies.

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Site-specific glycan analysis of epidermal growth factor receptor (EGFR)

Project description:This study provides site-specific profiles of asparagine-linked and serine/threonine-linked glycosylations on ErbB2, a therapeutic target RTK for ErbB2-positive cancer, through structural analysis of recombinant ErbB2 extracellular region and endogenous ErbB2 from ErbB2-positive breast cancer cells. Furthermore, comparison of the N-glycosylated structures of the extracellular regions of ErbB2 and its homologue, the epidermal growth factor receptor (EGFR), showed differences in the distribution and density of N-glycans on both molecules, providing new insights into the different activation mechanisms of ErbB2 and EGFR from a glycan perspective.

2024-05-24 | PXD039836 | Pride

Targeting Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) Expressing Bladder Cancer Using Combination Photoimmunotherapy (PIT).

Project description:Bladder cancer (BC) is heterogeneous and expresses various cell surface targets. Photoimmunotherapy (PIT) involves monoclonal antibodies (MAbs) conjugated to a photoabsorber (PA), IR Dye 700Dx, and then activated by near infra-red light (NIR) to specifically target tumors. We have demonstrated that tumors expressing EGFR can be targeted with PIT. However, PIT may be less effective when a tumor lacks "overwhelming" expression of a single target such as EGFR. We present a combinatorial PIT approach for targeting BC expressing EGFR and HER2, using PA- labeled panitumumab (pan) and trastuzumab (tra), respectively. Human BC tissues and cell lines were analyzed for EGFR and HER2 expression. Efficacy of PA-labeled MAbs singly and in combination was analyzed. About 45% of BC tissues stain for both EGFR and HER2. In vitro, the combination of pan IR700 and tra IR700 with NIR was more efficacious than either agent alone. Tumor xenografts treated with combination PIT showed significant tumor growth retardation. Combination PIT is a promising approach for treating BC with low/moderate expression of surface receptors. In addition, given the molecular heterogeneity of bladder cancer, targeting more than one surface receptor may allow for more effective cell death across different bladder tumors.

| S-EPMC6375935 | biostudies-literature

A Study of Poziotinib in Patients With Epidermal Growth Factor Receptor (EGFR) or Human Epidermal Growth Factor Receptor 2 (HER2) Activating Mutations in Advanced Malignancies

Project description:This is a Phase 2, open-label, multicenter study whose principal objectives are to evaluate the efficacy and safety/tolerability of poziotinib in five cohorts of 30 previously-treated patients each.

| 2322657 | ecrin-mdr-crc

Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S.

Project description:Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode.

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Association of epidermal growth factor receptor (EGFR) gene polymorphisms with endometriosis.

Project description:AimsTo investigate the association between polymorphism in the gene encoding the epidermal growth factor receptor (EGFR) and susceptibility to endometriosis among women in southwest China.MethodsA case-control study involving 201 endometriosis patients and 237 control women without endometriosis was carried out at West China Second Hospital of Sichuan University from June 2016 to December 2017. Two tag single-nucleotide polymorphisms (SNPs) of EGFR gene, rs11977660 and rs2072454 were selected, and the distribution of genotypes and alleles was compared between the 2 groups using the chi-squared test with 2-sided contingency tables.ResultsGenotype at rs11977660 was significantly associated with endometriosis (P < .05 for genotype and allele). T/T+C/T genotypes were associated with significantly higher risk of developing endometriosis than the C/C genotype (OR 2.129, 95%CI 1.411-3.212). No significant association was found between genotype at rs2072454 and endometriosis.ConclusionGenotypes with a T nucleotide at rs11977660 may significantly increase risk of endometriosis in Chinese.

| S-EPMC6831181 | biostudies-literature

Balancing Selectivity and Efficacy of Bispecific Epidermal Growth Factor Receptor (EGFR) × c-MET Antibodies and Antibody-Drug Conjugates.

Project description:Bispecific antibodies (bsAbs) and antibody-drug conjugates (ADCs) have already demonstrated benefits for the treatment of cancer in several clinical studies, showing improved drug selectivity and efficacy. In particular, simultaneous targeting of prominent cancer antigens, such as EGF receptor (EGFR) and c-MET, by bsAbs has raised increasing interest for potentially circumventing receptor cross-talk and c-MET-mediated acquired resistance during anti-EGFR monotherapy. In this study, we combined the selectivity of EGFR × c-MET bsAbs with the potency of cytotoxic agents via bispecific antibody-toxin conjugation. Affinity-attenuated bispecific EGFR × c-MET antibody-drug conjugates demonstrated high in vitro selectivity toward tumor cells overexpressing both antigens and potent anti-tumor efficacy. Due to basal EGFR expression in the skin, ADCs targeting EGFR in general warrant early safety assessments. Reduction in EGFR affinity led to decreased toxicity in keratinocytes. Thus, the combination of bsAb affinity engineering with the concept of toxin conjugation may be a viable route to improve the safety profile of ADCs targeting ubiquitously expressed antigens.

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