Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

Pharmaceuticals, Год журнала: 2021, Номер 14(6), С. 589 - 589

Опубликована: Июнь 18, 2021

Triple-negative breast cancer (TNBC) is a subset of with aggressive characteristics and few therapeutic options. The lack an appropriate target challenging issue in treating TNBC. Although high level expression epidermal growth factor receptor (EGFR) has been associated poor prognosis among patients TNBC, targeted anti-EGFR therapies have demonstrated limited efficacy for TNBC treatment both clinical preclinical settings. However, the advantage number clinically approved EGFR inhibitors (EGFRis), combination strategies explored as promising approach to overcome intrinsic resistance EGFRis. In this review, we analyzed literature on EGFRis other molecularly therapeutics or conventional chemotherapeutics understand current knowledge provide potential options treatment.

Язык: Английский

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Discovery of Dosimertinib, a Highly Potent, Selective, and Orally Efficacious Deuterated EGFR Targeting Clinical Candidate for the Treatment of Non-Small-Cell Lung Cancer

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 64(2), С. 925 - 937

Опубликована: Янв. 18, 2021

Osimertinib is a highly potent and selective third-generation epidermal growth factor receptor (EGFR) inhibitor, which provides excellent clinical benefits now standard-of-care therapy for advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, AZ5104, primary toxic metabolite of osimertinib, has caused unwanted toxicities. To address this unmet medical need, we initiated an iterative program focusing on structural optimizations osimertinib preclinical characterization, leading to the discovery potent, selective, orally efficacious deuterated EGFR-targeting candidate, dosimertinib. Preclinical studies revealed that dosimertinib demonstrated robust in vivo antitumor efficacy favorable PK profiles, but with lower toxicity than osimertinib. These data support further development treatment NSCLC. Dosimertinib received official approval China initiate phase I trial (registration numbers: CXHL2000060 CXHL2000061).

Язык: Английский

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Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors

European Journal of Medicinal Chemistry, Год журнала: 2021, Номер 216, С. 113300 - 113300

Опубликована: Фев. 21, 2021

Язык: Английский

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Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats

PeerJ, Год журнала: 2023, Номер 11, С. e15844 - e15844

Опубликована: Авг. 10, 2023

Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients reduce risk of opportunistic fungal infections. Our objective was investigate whether three triazole (voriconazole, itraconazole, and fluconazole) could change pharmacokinetics osimertinib in rats.The adult male Sprague-Dawley rats were randomly divided into four groups (n = 6): control (0.3% CMC-Na), voriconazole (20 mg/kg), itraconazole or fluconazole mg/kg) combined with (10 group. Tail vein blood samples collected heparin tubes at various time points within 0-48 h after administration. Osimrtinib's plasma concentration detected using HPLC-MS/MS system equipped a Waters XBridge C18 column, mobile phase consisting acetonitrile 0.2% formic acid water flow rate 0.5 mL/min.Co-administration increased Cmax by 58.04% 53.45%, respectively; AUC0-t 62.56% 100.98%, respectively. However, when co-administered only 13.91% 34.80%, respectively.Our results revealed that significantly changed rats, whereas it slightly affected itraconazole. This work will contribute more comprehensive understanding pharmacokinetic properties antifungals.

Язык: Английский

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Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib

BioDrugs, Год журнала: 2015, Номер 29(3), С. 167 - 183

Опубликована: Июнь 1, 2015

First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment armamentarium for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all inevitably develop acquired resistance these agents, primarily due secondary mutations, molecular aberrations affecting other signaling pathways, or transformation small-cell histology. It was hypothesized that development of second-generation TKIs broader inhibitory profiles could confer longer-lasting clinical activity overcome first-generation inhibitors. Here, we review afatinib, irreversible ErbB family blocker potently inhibits homodimers heterodimers formed by EGFR, human (HER)-2, HER3, HER4 receptors. In two phase III trials in mutation-positive NSCLC, first-line afatinib significantly improved progression-free survival (PFS) health-related quality life versus standard-of-care chemotherapy. Moreover, preplanned sub-analyses, overall harboring Del19 Afatinib has also demonstrated NSCLC who had progressed on erlotinib/gefitinib, particularly when combined cetuximab, offers 'treatment beyond progression' benefit paclitaxel chemotherapy alone. Furthermore, a recent study PFS second-line squamous cell carcinoma lung. The both relapsed/refractory settings may reflect its ability irreversibly inhibit members. well-defined safety profile characteristic gastrointestinal (diarrhea, stomatitis) cutaneous (rash/acne) adverse events.

Язык: Английский

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