6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity

Tsou, Hwei‐Ru; Mamuya, Nellie; Johnson, Bernard; Reich, Marvin F.; Gruber, Brian C.; Ye, Fei; Nilakantan, Ramaswamy; Shen, Ru; Discafani, Carolyn; Deblanc, Ronald; Davis, Rachel E.; Koehn, Frank E.; Greenberger, Lee M.; Wang, Yufen; Wissner, Allan

doi:10.1021/jm0005555

Cited by 257 publications

(250 citation statements)

References 27 publications

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“…25,51 The acrylamide derivative 10, belonging to the B-series of quinazolines, completely inhibited EGFR autophosphorylation 1 and 8 h after treatment at 1 μM concentration (96% and 99% inhibition, respectively). Substitution of the electrophilic warhead of 10 with a 3-aminopropanamide side chain led to compounds 11 (dimethylamino), 12 (piperidino), and 13 (morpholino), which gave EGFR percent inhibition 1 and 8 h after removal from the medium between 92% and 100%.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

et al. 2012

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Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with offtargets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

et al. 2012

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“…Also shown on Figure 1, for comparative purposes are the structures of two characteristic quinazolines with anti-tyrosine kinase activity (EGFR antagonists). 85 (5) Quinazoline mediated apoptosis in prostate cells: a mechanistic model of a novel action Growing evidence from this laboratory supports the concept that the mechanism of doxazosin and terazosin action against benign and malignant prostate cells occurs independently of targeting the a 1 -adrenoceptors. 83,86 It is tempting to propose that the apoptotic effects of these drugs may share mechanistic similarity with other quinazoline-based agents reported in the literature.…”

Section: (4) Quinazolines As Antitumor Agents: a Molecular Insightmentioning

confidence: 95%

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

Anglin

Glassman

Kyprianou

2002

Prostate Cancer Prostatic Dis

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a 1 -Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based a 1 -antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an a 1 -adrenoceptor independent mechanism potentially involving activation of the TGF-b signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived a 1 -adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases.

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“…16 -20 The ligand binds covalently to the cys-773, which is proximal to the ATP binding site. 20 The irreversible binding blocks EGFr function, leading to growth inhibition and apoptosis. 16 On the basis of these findings, we present the biological evaluation of a novel EGFr-TK irreversible inhibitor, N-{4- [(4,5-dichloro-2-fluorophenyl)amino] quinazolin-6-yl}acrylamide (ML03, Fig.…”

Section: Abstract: Carbon-11; Cancer; Biodistribution; Pet; Egfrmentioning

confidence: 99%

“…At different time points (10,20,30,40, 50 and 60 min), 5 mL of ether was added to blood/plasma and the vials were counted in a ␥-counter. One sample of blood and 1 of plasma were treated immediately with ether without incubation at 37°C (Time 0).…”

Section: Extraction and Stability Of [mentioning

confidence: 99%

Labeled EGFr‐TK irreversible inhibitor (ML03): In vitro and in vivo properties, potential as PET biomarker for cancer and feasibility as anticancer drug

Ortu

Ben-David

Rozen

et al. 2002

Intl Journal of Cancer

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Radiosynthesis of ML03 (N-{4 Key words: carbon-11; cancer; biodistribution; PET; EGFrGrowth factors mediate their pleiotropic actions by binding to and activating receptor tyrosine kinases. Epidermal growth factor receptor (EGFr, erb-B1) belongs to a family of proteins involved in the proliferation of normal and malignant cells. 1,2 The binding of activating ligands such as EGF, TGF ␣, AR, BTC or HB-EGF to the EGFr results in activation of the cytosolic kinase domain. Overexpression of EGFr is the hallmark of many human tumors such as breast cancer, glioma, laryngeal cancer, squamous cell carcinoma of the head and neck and prostate cancer. 3 Since the late 1980s continuous effort has been invested in the development of EGFr tyrosine kinase inhibitors as anti-neoplastic drugs. 4,5-11 Radioactively labeled small molecules with high affinity and selectivity for the tyrosine kinase domain of EGFr might offer a specific and sensitive tool to be used in positron emission tomography (PET) for diagnosis of tumors overexpressing EGFr. PET provides 3D and quantitative maps of the distribution of radioactive tracers within the human body and hence permits the measurement of physiological, biochemical and pharmacological function at the molecular level, both in healthy and pathological states. PET is based on the use of short half-life positron-emitting isotopes, such as 11 C (t 1/2 20.39 min.), 18 F (t 1/2 109.8 min.), 15 O (t 1/2 2.037 min.) and 13 N (t 1/2 9.965 min.). After injection of a suitable biomarker, the PET scan provides a mapping of the biomarker distribution and hence of a specific receptor, transporter or enzyme in the human body. Biomarkers with high selectivity for a specific receptor or enzyme might accumulate in those organs and tissues where the targeted protein is overexpressed. In the case of EGFr, its overexpression in human tumors could be non-invasively detected by labeling tyrosine kinase inhibitors with positron-emitting isotopes. The PET application of these potential biomarkers represents a new strategy for the diagnosis of EGFr-expressing tumors. [12][13][14] Moreover, the increasing demand to incorporate diagnostics into clinical studies of EGFr-targeted therapies suggests a potential future use of EGFrTK labeled inhibitors. These labeled inhibitors could help select patients for clinical trials. Cancer patients could undergo a non-invasive diagnostic PET study with labeled EGFrTK inhibitor, and if their tumor is found to overexpress EGFrTK, they could then be selected for a clinical trial that utilizes anti-EGFr therapy.In our previous work, 15 we synthesized, labeled and evaluated 4-(fluoroanilino)quinazoline derivatives as EGFrTK PET biomarkers. These molecules bind reversibly to the ATP binding site of the receptor and inhibit the autophosphorylation of the EGFrTK. Competition with intracellular ATP results in their fast dissociation from the EGFr kinase site, however, making these compounds ineffective as PET reporter probes. We therefore concluded that irreversible EGFr tyrosine kinase ...

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6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity

Cited by 257 publications

References 27 publications

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

Labeled EGFr‐TK irreversible inhibitor (ML03): In vitro and in vivo properties, potential as PET biomarker for cancer and feasibility as anticancer drug

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