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Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazoline core to selectively inhibit EGFR/HER2 tyrosine kinases. Twelve compounds (8a-8d, 9a, 9c, 9d, 10a, 10c, 11b, 14, and 15) showed nanomolar range of IC50 values on EGFR and/or HER2 kinases. Accordingly, a detailed structure activity relationship (SAR) was established. A molecular docking study demonstrated the favorable binding modes of 8d, 9b, 9d and 10d at the ATP active site of both kinases. A kinase selectivity profile performed for compound 8d showed great selectivity for EGFR and HER2. In addition, 8d, 9c, and 9d exerted selective promising cytotoxic activity over BT-474 cell line with IC50 values of 2.70, 1.82 and 1.95μM, respectively. From these results, we report analogs 8d, 9c, and 9d as promising candidates for the discovery of well-balanced compounds in terms of the kinase inhibitory potency and antiproliferative activity.
This article was published in the following journal.
Name: Bioorganic & medicinal chemistry letters
Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a l...
HER2 overexpression is identified on 20-30% breast cancer and other cancers at different levels. Although HER2 targeted monoclonal antibody combined with chemical drugs has shown improved outcomes in ...
A series of 4-arylamido-2-arylaminoprimidines bearing acrylamide pharmacophore were synthesized as potent EGFR inhibitors among which 9c (IC = 0.5872 nM), 9d (IC = 2.213 nM), or 9h (IC =...
Uveal melanoma is the most common intraocular primary malignant tumor in adults, and retinoblastoma is the one in children. Current mainstay treatment options include chemotherapy using conventional d...
The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule targeting agents prompted us to design and to develop single agents which possess both epidermal gro...
The Epidermal Growth Factor Receptor (EGFR) is a validated target for the treatment of cancer, and agents targeting EGFR such as erlotinib (Tarceva®) are approved by the FDA for treatment...
AEE788 is an orally active, reversible, small-molecule, multi-targeted kinase inhibitor with potent inhibitory activity against ErbB and VEGF receptor family of tyrosine kinases. It has an...
This phase I trial studies the side effects and best dose of necitumumab when given together with epidermal growth factor receptor (EGFR) inhibitor AZD9291 in treating patients with EGFR-p...
The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutat...
YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) targets both the T790M mutation and activating EGFR mutations while sparing wild...
A humanized monoclonal antibody against the ERBB-2 RECEPTOR (HER2). As an ANTINEOPLASTIC AGENT, it is used to treat BREAST CANCER where HER2 is overexpressed.
Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.
A family of non-receptor, PROLINE-rich protein-tyrosine kinases.
A cytoplasmic receptor and peroxin that contains a series of TETRACOTIPEPTIDE REPEATS and binds to PEROXISOME TARGETING SIGNAL 1 (SKL-type). It is essential for protein import into PEROXISOMES; mutations in the PEX5 gene are associated with PEROXISOMAL DISORDERS such as ZELLWEGER SYNDROME.
A cytoplasmic receptor and peroxin that contains a series of WD40 REPEATS and binds to PEROXISOME TARGETING SIGNAL 2. It is essential for protein import into PEROXISOMES; mutations in the human PEX7 gene are associated with PEROXISOMAL DISORDERS such as Type 1 CHONDRODYSPLASIA PUNCTATA, RHIZOMELIC.
An assay is an analytic procedure for qualitatively assessing or quantitatively measuring the presence or amount or the functional activity of a target entity. This can be a drug or biochemical substance or a cell in an organism or organic sample. ...