Molecular targeted therapy for anticancer treatment

Experimental & Molecular Medicine, Год журнала: 2022, Номер 54(10), С. 1670 - 1694

Опубликована: Окт. 12, 2022

Abstract Since the initial clinical approval in late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served a fundamental backbone precision medicine cancer treatment. These approaches are now used clinically first-line various human cancers. Compared to conventional chemotherapy, have efficient with fewer side effects. However, emergence drug resistance is major drawback therapy, several strategies been attempted improve efficacy by overcoming such resistance. Herein, we summarize current knowledge regarding agents, including classification, brief biology target kinases, mechanisms action, examples perspectives future development.

Язык: Английский

---

Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial

Journal of Thoracic Oncology, Год журнала: 2020, Номер 15(12), С. 1907 - 1918

Опубликована: Сен. 9, 2020

Язык: Английский

---

FDA- and EMA-Approved Tyrosine Kinase Inhibitors in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: Safety, Tolerability, Plasma Concentration Monitoring, and Management

Biomolecules, Год журнала: 2019, Номер 9(11), С. 668 - 668

Опубликована: Окт. 30, 2019

Non-small-cell lung cancer (NSCLC) is the most common form of primary cancer. The discovery several oncogenic driver mutations in patients with NSCLC has allowed development personalized treatments based on these specific molecular alterations, particular tyrosine kinase (TK) domain epidermal growth factor receptor (EGFR) gene. Gefitinib, erlotinib, afatinib, and osimertinib are TK inhibitors (TKIs) that specifically target EGFR currently approved by Food Drug Administration (FDA) European Medicines Agency (EMA) as first line treatment for sensitive EGFR-mutant patients. However, four drugs associated severe adverse events (AEs) can significantly impact patient health-related quality life monitoring. EGFR-TKIs commonly used together other types medication substantially interact. Here, we review approaches management TKI-AEs advanced to promote benefits minimize risk TKI discontinuation. We also consider potential TKI–drug interactions discuss usefulness plasma concentration monitoring TKIs chromatographic mass spectrometry guide clinical decision-making. Adjusting appropriate therapeutic strategies drug doses may improve performance therapy prognosis EGFR-mutated NSCLC.

Язык: Английский

---

Discovery of a novel series of substituted quinolines acting as anticancer agents and selective EGFR blocker: Molecular docking study

Bioorganic & Medicinal Chemistry Letters, Год журнала: 2021, Номер 44, С. 128118 - 128118

Опубликована: Май 17, 2021

Язык: Английский

---

Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Сен. 14, 2020

Abstract Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show while AXL-low expressing EGFR mutated lung cancer ( mut-LC) cells are more sensitive osimertinib than AXL-high mut-LC cells, a small population emerge tolerance. The mediated by increased expression and phosphorylation of insulin-like factor-1 receptor (IGF-1R), caused induction its transcription FOXA1. IGF-1R maintains association with adaptor proteins, Gab1 IRS1, in presence restores survival signal. In AXL-low-expressing cell-derived xenograft patient-derived models, transient inhibition combined continuous treatment could eradicate tumors prevent regrowth even after cessation osimertinib. These results indicate optimal tolerant signals may dramatically improve outcome mut-LC.

Язык: Английский

---

Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression

Pharmacology & Therapeutics, Год журнала: 2021, Номер 232, С. 107992 - 107992

Опубликована: Окт. 1, 2021

Язык: Английский

---

The state of the art in secondary pharmacology and its impact on the safety of new medicines

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(7), С. 525 - 545

Опубликована: Май 21, 2024

Язык: Английский

---

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents

BMC Chemistry, Год журнала: 2024, Номер 18(1)

Опубликована: Янв. 3, 2024

Abstract The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects anticancer drugs. In this study, a series uracil–azole hybrids were designed synthesized. activity, along with computational studies: molecular docking, dynamic simulation, density functional theory, ADME properties also, evaluated. compounds synthesized by using 3-methyl-6-chlorouracil as starting material. Cytotoxicity was determined MTT assay in breast carcinoma cell line (MCF-7) Hepatocellular (HEPG-2). These derivatives demonstrated powerful inhibitory activity against hepatocellular lines comparison Cisplatin positive control. Among these compounds, 4j displayed best selectivity profile good IC 50 values 16.18 ± 1.02 7.56 5.28 µM MCF-7 HEPG-2 respectively. Structure–activity relationships revealed that variation potency affected various substitutions benzyl moiety. docking output showed bind well active site EGFR formed stable complex protein. DFT used investigate reactivity descriptors 4a . outputs can be considered potential agents.

Язык: Английский

---

Safety Profile of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Disproportionality Analysis of FDA Adverse Event Reporting System

Scientific Reports, Год журнала: 2020, Номер 10(1)

Опубликована: Март 16, 2020

Abstract Adverse event reports submitted to the US Food and Drug Administration (FDA) were analyzed map safety profile of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). We conducted a disproportionality analysis adverse events (AEs) EGFR-TKIs (gefitinib, erlotinib, afatinib, osimertinib) by data mining using FDA reporting system (AERS) database, calculating odds ratios (ROR) with 95% confidence intervals. The AERS database contained 27,123 EGFR-TKI-associated AERs within period from January 1, 2004 March 31, 2018. Thirty-three preferred terms (PTs) selected for analysis, significant RORs most commonly observed in skin, nail, gastrointestinal tract, hepatic, eyes, lungs. Unexpected drug reactions found “intestinal obstruction” “hypokalaemia” gefitinib “hyponatraemia” gefitinib, erlotinib “alopecia”in “hair abnormal” but not “nausea” “vomiting” listed on labels. results this study are consistent clinical observation, suggesting usefulness pharmacovigilance research should be corroborated real-world FAERS data.

Язык: Английский

---

Interstitial lung disease in patients treated with Cyclin-Dependent Kinase 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials

The Breast, Год журнала: 2022, Номер 62, С. 162 - 169

Опубликована: Фев. 22, 2022

Cyclin-Dependent Kinase (CDK) 4/6 inhibitors have shown significant clinical activity in cancer patients. However, some concerns regarding rare adverse events (AEs) occurred including interstitial lung disease (ILD)/pneumonitis, for which data are deficient. The aim of this study was to evaluate the overall incidence and risk ILD/pneumonitis related CDK4/6 randomized controlled trials (RCTs).Electronic databases ClinicalTrials.gov were searched from inception October 1, 2021 RCTs reporting occurrence LD/pneumonitis patients treated with inhibitors. Peto odds ratios (Peto ORs) 95% confidence intervals (CIs) used pool study.12 a total 16,060 eligible. all-grade 1.6% (131/8407) treatment group compared 0.7% (50/7349) control group. significantly increased pooled OR 2.12 (95% CI [1.57, 2.86], P < 0.00001) no heterogeneity (I2 = 0%, χ2 0.98). A higher grade 3 or also observed (0.2%, 16/7087) (0.05%, 3/6617) 3.22 [1.28, 8.09], 0.01) 0.62). Two 5 pneumonitis reported included studies. Subgroup analyses did not show any difference.The controls. awareness these AEs application should be enhanced. Further studies required validate mechanisms factors

Язык: Английский

---