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2.
Eur J Med Chem ; 233: 114249, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35259690

RESUMO

Pan-HER inhibitors exhibit extensive biological activity and offer unique advantages and usually bind to targets in an irreversible manner. Owing to the off-target toxicity of irreversible inhibitors, reversible pan-HER inhibitors are desirable. Herein, we describe the process of N-(ring structure fused phenyl)quinazoline-4-amine-based design, synthesis, and biological evaluation of pan-HER inhibitors in vitro and in vivo. Compound C5, with the molecular skeleton of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine, displayed irreversible binding just like other effective pan-HER inhibitors. To our surprise, compound C6, which possessed the same skeleton, was found to be a high-strength reversible pan-HER inhibitor. This compound was capable of inhibiting HER1s (such as EGFR T790M/L858R and WT), HER2, and HER4 and can be considered as a breakthrough in the development of pan-HER inhibitors. Altogether, N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine can serve as an effective molecular skeleton for developing both reversible and irreversible pan-HER inhibitors in the following discovery of antitumor drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Humanos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
3.
Biomed Pharmacother ; 148: 112756, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35228064

RESUMO

The 2019 corona virus disease (COVID-19) has caused a global chaos, where a novel Omicron variant has challenged the healthcare system, followed by which it has been referred to as a variant of concern (VOC) by the World Health Organization (WHO), owing to its alarming transmission and infectivity rate. The large number of mutations in the receptor binding domain (RBD) of the spike protein is responsible for strengthening of the spike-angiotensin-converting enzyme 2 (ACE2) interaction, thereby explaining the elevated threat. This is supplemented by enhanced resistance of the variant towards pre-existing antibodies approved for the COVID-19 therapy. The manuscript brings into light failure of existing therapies to provide the desired effect, however simultaneously discussing the novel possibilities on the verge of establishing suitable treatment portfolio. The authors entail the risks associated with omicron resistance against antibodies and vaccine ineffectiveness on one side, and novel approaches and targets - kinase inhibitors, viral protease inhibitors, phytoconstituents, entry pathways - on the other. The manuscript aims to provide a holistic picture about the Omicron variant, by providing comprehensive discussions related to multiple aspects of the mutated spike variant, which might aid the global researchers and healthcare experts in finding an optimised solution to this pandemic.


Assuntos
COVID-19/fisiopatologia , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Catepsinas/metabolismo , Receptores ErbB/antagonistas & inibidores , Humanos , Esquemas de Imunização , Imunização Secundária , Fitoterapia/métodos , Plantas Medicinais , Ligação Proteica/fisiologia , Domínios e Motivos de Interação entre Proteínas/fisiologia , Elementos Estruturais de Proteínas/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêutico
4.
J Enzyme Inhib Med Chem ; 37(1): 832-843, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35260020

RESUMO

This paper described our efforts to develop dianilinopyrimidines as novel EGFR inhibitors. All the target compounds were tested for inhibitory effects against wild type EGFR (EGFRwt) and three tumour cells, including A549, PC-3, and HepG2. Some of the compounds performed well in antitumor activities. Especially, compound 4c 2-((2-((4-(3-fluorobenzamido)phenyl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)-N-methylthiophene-3-carboxamide showed higher anti-tumour activities than Gefitinib. The IC50 values of compound 4c against A549, PC-3, and HepG2. reached 0.56 µM, 2.46 µM, and 2.21 µM, respectively. In addition, further studies indicated that compound 4c could induce apoptosis against A549 cells and arrest A549 cells in the G2/M phase. Molecular docking studies showed that compound 4c could closely interact with EGFR. Generally, compound 4c was the potential for developing into an anti-tumour drug.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
5.
Chem Commun (Camb) ; 58(16): 2726-2729, 2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35113095

RESUMO

Epidermal growth factor receptor (EGFR) targeted nano-drugs facilitate effective diagnosis and treatment of cancer. Herein, the therapeutic efficacy of nano-drugs targeting EGFR was evaluated from the perspective of cell entry efficiency and induced cell mechanical properties using force tracing and nano-indentation techniques at the single particle/cell level in real time.


Assuntos
Nanopartículas/química , Poliaminas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Poliaminas/química , Inibidores de Proteínas Quinases/química
6.
Head Neck ; 44(5): 1192-1205, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35224804

RESUMO

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease with poor survival. Although epidermal growth factor receptor (EGFR)-targeting antibody cetuximab improves survival in some settings, responses are limited suggesting that alternative approaches are needed. METHODS: We performed a high throughput drug screen to identify EGFR inhibitor-based synergistic combinations of clinically advanced inhibitors in models resistant to EGFR inhibitor monotherapies, and then performed downstream validation experiments on prioritized synergistic combinations. RESULTS: From our screen, we re-discovered known synergistic EGFR inhibitor combinations with FGFR or IGF-1R inhibitors that were broadly effective and also discovered novel synergistic combinations with XIAP inhibitor and DNMT inhibitors that were effective in only a subset of models. CONCLUSIONS: Conceptually, our data identify novel synergistic combinations that warrant evaluation in future studies, and suggest that some combinations, although highly synergistic, will require parallel companion diagnostic development to be effectively advanced in patients.


Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
7.
Oncogene ; 41(14): 2026-2038, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35173310

RESUMO

The emergence of RAS/RAF mutant clone is the main feature of EGFR inhibitor resistance in KRAS wild-type colon cancer. However, its molecular mechanism is thought to be multifactorial, mainly due to cellular heterogeneity. In order to better understand the resistance mechanism in a single clone level, we successfully isolated nine cells with cetuximab-resistant (CR) clonality from in vitro system. All CR cells harbored either KRAS or BRAF mutations. Characteristically, these cells showed a higher EMT (Epithelial to mesenchymal transition) signature, showing increased EMT markers such as SNAI2. Moreover, the expression level of CXCL1/5, a secreted protein, was significantly higher in CR cells compared to the parental cells. In these CR cells, CXCL1/5 expression was coordinately regulated by SNAI2/NFKB and transactivated EGFR through CXCR/MMPI/EGF axis via autocrine singling. We also observed that combined cetuximab/MEK inhibitor not only showed growth inhibition but also reduced the secreted amounts of CXCL1/5. We further found that serum CXCL1/5 level was positively correlated with the presence of RAS/RAF mutation in colon cancer patients during cetuximab therapy, suggesting its role as a biomarker. These data indicated that the application of serum CXCL1/5 could be a potential serologic biomarker for predicting resistance to EGFR therapy in colorectal cancer.


Assuntos
Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Cetuximab/uso terapêutico , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
8.
Life Sci ; 296: 120408, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35202641

RESUMO

AIMS: The adenosine-to-inosine (A-to-I) RNA editing controlled by the editing genes are known to diversify transcripts in human. Aberrant A-to-I editing due to dysregulation of the editing genes are involved in cancer development. However, it is still largely unclear how single nucleotide polymorphisms (SNPs) in the A-to-I editing genes confer to recurrence and/or drug resistance of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: In this study, we systematically evaluated and validated the role of twenty-eight potential functional genetic variants in four A-to-I editing genes (ADAR, ADARB1, ADARB2 and AIMP2) in prognosis of NSCLC patients receiving EGFR-TKIs. KEY FINDINGS: We identified the ADAR rs1127309, rs1127317, and rs2229857 SNPs markedly contributing to prognosis of patients treated with EGFR-TKIs. Interestingly, SNP rs1127317 locating in the ADAR 3'-untranslated region regulates gene expression in an allele-specific manner via modulating binding of miR-454-5p in cells. In support of this, patients with the rs1127317 C allele correlated with elevated ADAR expression in tumors showed profoundly shorten survival after EGFR-TKIs therapy compared to the A allele carriers. Silencing of ADAR notably enhanced gefitinib sensitivities of NSCLC cells. SIGNIFICANCE: Our findings highlight the importance of the A-to-I RNA editing in drug resistance and nominate ADAR as a potential therapeutic target for unresectable NSCLC.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenosina Desaminase/genética , Antineoplásicos/farmacologia , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Ligação a RNA/genética , Regiões 3' não Traduzidas , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Gefitinibe/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único
9.
Molecules ; 27(3)2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35164092

RESUMO

Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug's ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Desenho de Fármacos , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Conformação Proteica/efeitos dos fármacos
10.
Oxid Med Cell Longev ; 2022: 6119737, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35111279

RESUMO

As the main active ingredients of Panax ginseng, ginsenosides possess numerous bioactivities. Epidermal growth factor receptor (EGFR) was widely used as a valid target in anticancer therapy. Herein, the EGFR targeting activities of 20(S)-ginsenoside Rh2 (20(S)-Rh2) and the relationship of their structure-activity were investigated. Homogeneous time-resolved fluorescence assay showed that 20(S)-Rh2 significantly inhibited the activity against EGFR kinase. 20(S)-Rh2 was confirmed to effectively inhibited cell proliferation in a dose-dependent manner by MTT assay. Furthermore, quantitative real-time PCR and western blotting analysis revealed that 20(S)-Rh2 inhibited A549 cells growth via the EGFR-MAPK pathway. Meanwhile, 20(S)-Rh2 could promote cell apoptosis, block cell cycle, and reduce cell migration of A549 cells, respectively. In silico, the result suggested that both hydrophobic interactions and hydrogen-bonding interactions could contribute to stabilize their binding. Molecular dynamics simulation showed that the side chain sugar moiety of 20(S)-Rh2 was too flexible to be fixed at the active site of EGFR. Collectively, these findings suggested that 20(S)-Rh2 might serve as a potential EGFR tyrosine kinase inhibitor.


Assuntos
Receptores ErbB/antagonistas & inibidores , Ginsenosídeos/química , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Panax/química , Panax/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
11.
Chem Biol Interact ; 355: 109838, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35123995

RESUMO

A novel oxygen-containing heterocyclic linked 1H-benzo[f]chromene moieties (4a-g) and (6a-g) with anti-proliferative activity against cancer cell lines was designed, synthesized, and established on the basis of spectral data. All the prepared compounds were evaluated in vitro for their anti-proliferative activity against MCF-7, HCT-116, HepG-2 cell lines and normal cell lines HFL-1, WI-38. Compounds 4a, 4b, and 6e exhibited good activity against MCF-7, HCT-116, and HepG-2 cell lines, comparable to that of Vinblastine and Doxorubicin, and weak active against normal cell lines. Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds 4a, 4b, and 6e on the more sensitive cell line MCF-7 were studied. We found that compounds 4a, 4b, and 6e induce cell cycle arrest at G2/M phases for MCF-7 treated cells compared to untreated cells, which causes apoptosis and inhibits both the topoisomerase I and II enzymes. In addition, compounds 4a and 4b exhibited comparable inhibitory activity on tyrosine kinase receptors EGFR and VEGFR-2 kinases to that of the reference protein kinases inhibitor Sorafenib. The in silico molecular docking of the most active compounds into the active sites of EGFR kinase and Topo I & II enzymes provides us with a reasonable clarification of the interpreted biological data.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo I/química , Receptores ErbB/antagonistas & inibidores , Naftóis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Naftóis/metabolismo , Naftóis/farmacologia , Relação Estrutura-Atividade , Termodinâmica , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
Molecules ; 27(4)2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35208952

RESUMO

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7-18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.


Assuntos
Antineoplásicos , Chalconas , Inibidores de Ciclo-Oxigenase 2 , Proteínas de Neoplasias , Neoplasias , Inibidores de Proteínas Quinases , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Humanos , Estrutura Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
13.
Sci Rep ; 12(1): 2167, 2022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-35140316

RESUMO

Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) remains an issue of concern. We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 years). Uncommon EGFR mutation subtypes were significantly variable enriched in de novo resistance. The remaining sensitizing EGFR mutation subtypes (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-ß, p53 and ß-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6 × 10-4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36-73%] compared to IRs/LTRs [range 4-22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4/6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80-7.31, p-value < 0.001]. The presence of CDK4/6 amplification in pretreatment specimen serves as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Biomarcadores , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Amplificação de Genes , Genes erbB-1 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do Tratamento
14.
Mol Cancer ; 21(1): 43, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35144642

RESUMO

BACKGROUND: Identification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance. METHODS: METTL7B-overexpressed LUAD cell lines, gefitinib and osimertinib-resistant Cell-Derived tumor Xenograft (CDX) and Patient-Derived tumor Xenograft (PDX) mouse models were employed to evaluate the role of METTL7B in TKIs resistance. Ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was used to identify the metabolites regulated by METTL7B. Methylated RNA immunoprecipitation (MeRIP)-qPCR analysis was performed to measure the N6-methyladenosine (m6A) status of mRNA of METTL7B targeted genes. Gold nanocluster-assisted delivery of siRNA targeting METTL7B (GNC-siMETTL7B) was applied to evaluate the effect of METTL7B in TKIs resistance. RESULTS: Increased expression of METTL7B was found in TKIs-resistant LUAD cells and overexpression of METTL7B in LUAD cells induced TKIs resistance both in vitro and in vivo. Activated ROS-metabolism was identified in METTL7B-overexpressed LUAD cells, accompanied with upregulated protein level of GPX4, HMOX1 and SOD1 and their enzymatic activities. Globally elevated m6A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m6A modification of GPX4, HMOX1 and SOD1 mRNA. Knock-down of METTL7B by siRNA re-sensitized LUAD cells to gefitinib and osimertinib both in vitro and in vivo. CONCLUSIONS: This study uncovered a new critical link in METTL7B, glutathione metabolism and drug resistance. Our findings demonstrated that METTL7B inhibitors could be used for reversing TKIs resistance in LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Proteínas de Transporte , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Cromatografia Líquida , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Espectrometria de Massas em Tandem , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Future Oncol ; 18(9): 1159-1169, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35109665

RESUMO

Background: The role of adjuvant EGFR tyrosine kinase inhibitors (TKIs) in resected EGFR-mutated non-small-cell lung cancer (NSCLC) remains unclear. Materials & methods: We evaluated pooled hazard ratio and 95% CI for disease-free survival, overall survival and prespecified subgroups. Results: Seven prospective studies with 1288 patients were included in the meta-analysis. Adjuvant EGFR TKIs significantly improved disease-free survival in EGFR-mutated resected NSCLC (HR: 0.41; 95% CI: 0.24-0.70) and in all subgroups. However, the overall survival benefit was not significant (HR: 0.65; 95% CI: 0.36-1.17). The benefit of adjuvant TKIs may be associated with TKI regimens, treatment duration, pathological stage and EGFR mutation type. Conclusion: Adjuvant EGFR TKIs significantly improved disease-free survival and nonsignificantly improved overall survival in resected EGFR-mutated NSCLC.


For lung cancer patients who undergo radical surgery and whose tumors have EGFR mutation (a specific gene alteration in the tumor tissue), the optimal treatment following surgery is unclear. We summarized the available studies to compare the efficacy of anti-EGFR targeted therapies (EGFR inhibitors) with chemotherapy in patients after surgery. We found patients who received EGFR inhibitors after surgery had longer survival without disease recurrence, and a tendency toward longer overall survival than patients who received chemotherapy or no further therapy. The different treatment regimes, treatment duration, tumor stage and EGFR mutation type may impact the efficacy of EGFR inhibitors in these patients after undergoing surgery.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimioterapia Adjuvante , Terapia Combinada , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Inibidores de Proteínas Quinases/administração & dosagem
16.
Anticancer Res ; 42(3): 1615-1622, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35220259

RESUMO

BACKGROUND/AIM: Non-small cell lung cancers (NSCLCs) harboring uncommon epidermal growth factor receptor (EGFR) mutations are heterogeneous and show variable prevalence and clinical responses to EGFR tyrosine kinase inhibitors. We investigated the characteristics of uncommon EGFR mutations and the clinical efficacy of afatinib in patients with NSCLC harboring uncommon EGFR mutations. PATIENTS AND METHODS: In this multicenter, retrospective study, we analyzed patients with NSCLC with uncommon EGFR mutations in 16 South Korean institutes. Mutations were categorized according to their incidence: 1) major uncommon mutations (G719X and L861Q), 2) compound mutations, and 3) minor uncommon mutations (exon 20 insertion, S768I, and de novo T790M). RESULTS: Of 703 patients with EGFR-mutant NSCLC, 64 (9.1%) had uncommon EGFR mutations. Afatinib demonstrated activity against tumors harboring major uncommon mutations [median time of treatment (TOT): 20.3 months, 95% confidence interval (CI)=15.1-25.5; overall survival (OS): 30.6 months, 95% CI=26.3-34.8] and compound mutations (median TOT: 12.3 months, 95% CI=7.7-17.0; OS: 29.1 months, 95% CI=20.4-37.7) but not against tumors harboring minor uncommon mutations (median TOT: 3.8 months, 95% CI=1.7-6.0; OS: 8.5 months, 95% CI=5.2-11.7). The S768I mutation was present in 14 patients (1.99%). The median TOT and OS were not significantly different between S768I mutations and resistant exon 20 mutations. CONCLUSION: Afatinib is effective in patients with NSCLC harboring major uncommon and compound EGFR mutations.


Assuntos
Afatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Afatinib/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Éxons , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Seul , Fatores de Tempo , Resultado do Tratamento
17.
Science ; 375(6579): eabf5546, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35084981

RESUMO

Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Interneurônios/citologia , Células-Tronco Neurais/fisiologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Encéfalo/embriologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Carcinogênese , Linhagem da Célula , Proliferação de Células , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Interneurônios/fisiologia , Perda de Heterozigosidade , Células-Tronco Neurais/citologia , Organoides , RNA-Seq , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
18.
Cell Death Dis ; 13(1): 41, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013118

RESUMO

Despite the great advances in target therapy, lung cancer remains the top cause of cancer-related death worldwide. G protein-coupled receptor neurokinin-1 (NK1R) is shown to play multiple roles in various cancers; however, the pathological roles and clinical implication in lung cancer are unclarified. Here we identified NK1R as a significantly upregulated GPCR in the transcriptome and tissue array of human lung cancer samples, associated with advanced clinical stages and poor prognosis. Notably, NK1R is co-expressed with epidermal growth factor receptor (EGFR) in NSCLC patients' tissues and co-localized in the tumor cells. NK1R can crosstalk with EGFR by interacting with EGFR, transactivating EGFR phosphorylation and regulating the intracellular signaling of ERK1/2 and Akt. Activation of NK1R promotes the proliferation, colony formation, EMT, MMP2/14 expression, and migration of lung cancer cells. The inhibition of NK1R by selective antagonist aprepitant repressed cell proliferation and migration in vitro. Knockdown of NK1R significantly slowed down the tumor growth in nude mice. The sensitivity of lung cancer cells to gefitinib/osimertinib is highly increased in the presence of the selective NK1R antagonist aprepitant. Our data suggest that NK1R plays an important role in lung cancer development through EGFR signaling and the crosstalk between NK1R and EGFR may provide a potential therapeutic target for lung cancer treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores da Neurocinina-1/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Fosforilação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Receptores da Neurocinina-1/genética , Transdução de Sinais
19.
Bioorg Med Chem Lett ; 58: 128524, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34995690

RESUMO

A similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structures related to 1,5-dihydroxy-9H-xanthen-9-one, a previously established EGFR-TK inhibitor. Compounds were virtually screened and selected for bioactivity testing revealed 5 candidates, mostly displayed stronger antiproliferative activities than erlotinib with IC50 values between 0.95 and 17.71 µM against overexpressed EGFR-TK cancer cell lines: A431 and HeLa. NSC107228 displayed the strongest antiproliferative effects with IC50 values of 2.84 and 0.95 µM against A431 and HeLa cancer cell lines, respectively. Three compounds, NSC81111, NSC381467 and NSC114126 inhibited EGFR-TK with IC50 values between 0.15 and 30.18 nM. NSC81111 was the best inhibitor with IC50 = 0.15 nM. Molecular docking analysis of the 3 compounds predicted hydrogen bonding and hydrophobic interactions with key residues were important for the bioactivities observed. Furthermore, calculations of the physicochemical properties suggest the compounds are drug-like and are potentially active orally.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Oxigênio/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Xantenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , National Cancer Institute (U.S.) , Oxigênio/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Estados Unidos , Xantenos/síntese química , Xantenos/química
20.
Bioorg Med Chem Lett ; 58: 128529, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35007724

RESUMO

A novel series of benzothiazole-based derivatives linked to various amino acids and their corresponding ethyl ester analogues were prepared and were initially evaluated for their anticancer activity againstMCF-7 and HepG-2 and were further assessed as VEGFR-2 inhibitors. All the newly synthesized benzothiazole derivatives showed promising cytotoxic activities against the tested cell lines. Derivatives exhibited potent cytotoxic and VEGFR-2 inhibitory activities were then evaluated further as anticancer agents against the resistant MDA-MB-231 and as EGFR inhibitors. The carboxylic acid derivatives 10-12 and their ester analogues 21-23 displayed the highest anticancer activities with IC50 of 0.73-0.89 µM, against MCF-7 and IC50 of 2.54-2.80 µM, against HepG-2; compared to doxorubicin (IC50 = 1.13 and 2.75 µM, respectively); also they showed safety towards the normal cell line, the ethyl ester derivatives 21-23 showed a potent activity against the resistant MDA-MB-231 cell line with IC50 of 5.45-7.28 µM, relative to doxorubicin (IC50 = 7.46 µM) surpassing their carboxylic acid analogues 10-12 (IC50 of 8.88-11.02 µM). Furthermore, the promising derivatives 10-12 and 21-23 displayed promising VEGFR-2 inhibitory activity (IC50 = 0.15-0.19 µM) comparable to that of sorafenib (IC50 = 0.12 µM). Against EGFR, the ethyl ester derivatives 21-23 showed superior inhibitory activity relative to the used reference standard, erlotinib, with IC50 of 0.11-0.16 vs. 0.18 µM, respectively. The QSAR study revealed that the molecular bulkiness and molecular partial charge distribution govern the kinase inhibition potency in this series. Furthermore, the molecular docking study in VEGFR-2 active site showed that the novel synthesized benzothiazole derivatives adopted the common binding pattern of type II PK inhibitors.


Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/síntese química , Antineoplásicos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
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