Tyrosine Kinase Inhibitors. 8. An Unusually Steep Structure−Activity Relationship for Analogues of 4-(3-Bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a Potent Inhibitor of the Epidermal Growth Factor Receptor

Bridges, Alexander J.; Zhou, Hairong; Cody, Donna R.; Rewcastle, Gordon W.; McMichael, Amy; Showalter, H. D. Hollis; Fry, David W.; Kraker, and Alan J.; Denny, William A.

doi:10.1021/jm9503613

Cited by 293 publications

(267 citation statements)

References 30 publications

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“…In principle, the long-lasting effect observed on EGFR autophosphorylation could be ascribed to different phenomena: (i) accumulation of the inhibitor in cells, as previously demonstrated for some reversible quinazolines; 66 (ii) conversion of the competitive inhibitor into an irreversible one at the active site of the enzyme (mechanism-based inhibition), as described for other β-aminocarbonyl compounds; 38 (iii) generation of the corresponding reactive acrylamide, as described for aryl β-aminoethyl ketones that have potential application as prodrugs of unsaturated ketones. 67 As previously described, 54,66 some reversible quinazoline EGFR inhibitors are sequestered in cells generating falsepositive results in the autophosphorylation assay based on the 8 h washout protocol. As an example, the fully reversible compound 1, which is strongly sequestered in cells, produced 46.4% ± 6.7% inhibition of EGFR autophosphorylation (A459 cells) at 1 μM concentration 8 h after removal from the medium.…”

Section: ■ Results and Discussionmentioning

confidence: 81%

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: 81%

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

et al. 2012

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“…Eleven of the 22 inhibitors were known a priori to be potent inhibitors of HER1 and HER2 kinase activity (Bridges et al, 1996;Fry et al, 1998). AG1478, , is the prototype for this class of compounds and is commonly used as a potent and selective inhibitor of HER1 in laboratory models.…”

Section: Resultsmentioning

confidence: 99%

Differential sensitivity of cancer cells to inhibitors of the epidermal growth factor receptor family

Bishop

Myers²,

Robey

et al. 2002

Oncogene

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“…6C). Furthermore, pretreatment of cell cultures with another structurally unrelated EGFR tyrosine kinase inhibitor, compound 56 (7,26,32), also inhibited AVP-induced ERK-1/2 phosphorylation.…”

Section: Role Of Pkc Src [Ca 2ϩ ] I and Egfr In Avp-stimulated Ermentioning

confidence: 96%

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

Chiu

Santiskulvong

et al. 2002

American Journal of Physiology-Cell Physiology

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Here, we demonstrate that arginine vasopressin (AVP) induces multiple intracellular signal transduction pathways in rat intestinal epithelial IEC-18 cells via a V 1A receptor. Addition of AVP to these cells induces a rapid and transient increase in cytosolic Ca 2ϩ concentration and promotes protein kinase D (PKD) activation through a protein kinase C (PKC)-dependent pathway, as revealed by in vitro kinase assays and immunoblotting with an antibody that recognizes autophosphorylated PKD at Ser 916 . AVP also stimulates the tyrosine phosphorylation of the nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) and promotes Src family kinase phosphorylation at Tyr 418 , indicative of Src activation. AVP induces extracellular signal-related kinase (ERK)-1 (p44 mapk ) and ERK-2 (p42 mapk ) activation, a response prevented by treatment with mitogen-activated protein kinase kinase (MEK) inhibitors (PD-98059 and U-0126), specific PKC inhibitors (GF-I and Ro-31-8220), depletion of Ca 2ϩ (EGTA and thapsigargin), selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (tyrphostin AG-1478, compound 56), or the selective Src family kinase inhibitor PP-2. Furthermore, AVP acts as a potent growth factor for IEC-18 cells, inducing DNA synthesis and cell proliferation through ERK-, Ca 2ϩ -, PKC-, EGFR tyrosine kinase-, and Src-dependent pathways. arginine vasopressin; protein kinase D; protein kinase C; Src; proline-rich tyrosine kinase 2; intestinal epithelial proliferation THE SEQUENTIAL PROLIFERATION, lineage-specific differentiation, migration, and cell death of epithelial cells of the intestinal mucosa is a tightly regulated process that is modulated by a broad spectrum of regulatory peptides (8,36,70). The nontransformed IEC-6 and IEC-18 cells, derived from rat small intestinal crypt (56), have provided an in vitro model to examine intestinal epithelial cell migration, differentiation, and proliferation (16,27,58,70). Previous studies demonstrated that the proliferation and migration of these intestinal epithelial cells is regulated by a variety of polypeptide growth factors, including epidermal growth factor (EGF), insulin-like growth factor I, and hepatocyte growth factor, which act via single-pass transmembrane tyrosine kinase receptors (3,17,51). Neuropeptides and vasoactive peptides that signal through G protein-coupled receptors (GPCRs), characterized by seven-transmembrane helices, also act as potent cellular growth factors for a variety of cell types (63,64,66,67). However, the role of GPCRs and their ligands in intestinal epithelial cell signaling and proliferation remains poorly understood.The neurohypophysial nonapeptide arginine vasopressin (AVP), also known as antidiuretic hormone, is traditionally recognized for its role as a vasoconstrictor hormone acting on vascular smooth muscle cells and its antidiuretic effect via the renal collecting system. In addition to its function in the regulation of body fluid osmolality, vascular tone, and blood pressure, AVP acts as a growth-promo...

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Tyrosine Kinase Inhibitors. 8. An Unusually Steep Structure−Activity Relationship for Analogues of 4-(3-Bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a Potent Inhibitor of the Epidermal Growth Factor Receptor

Cited by 293 publications

References 30 publications

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

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

Differential sensitivity of cancer cells to inhibitors of the epidermal growth factor receptor family

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

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