Anilinodialkoxyquinazolines:  Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

VanBrocklin, Henry F.; Lim, Jeehee; Coffing, Stephanie L.; Hom, Darren L.; Negash, Kitaw; Ono, Michele Y.; Gilmore, Jennifer L.; Bryant, Ianthe; Riese, David J.

doi:10.1021/jm050607w

Cited by 31 publications

(17 citation statements)

References 54 publications

(135 reference statements)

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“…In the BaF3/EGFR + ErbB4 model system used in the present study, ErbB4 tyrosine phosphorylation may be the consequence of ErbB4 kinase activity (via ErbB4–ErbB4 homodimers) or may be the consequence of EGFR kinase activity (via EGFR–ErbB4 heterodimers). We have used an ErbB4 mutant (K751M) devoid of kinase activity [32] and the selective EGFR tyrosine kinase inhibitor PD153035 [33] to evaluate these two possibilities. In BaF3/EGFR cells, expression of wild-type ErbB4 or the ErbB4 K751M mutant enables stimulation of IL-3-independent proliferation by NRG2β (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist

Wilson

Mill

Gallo

et al. 2012

Biochemical Journal

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The ErbB4 receptor tyrosine kinase possesses both tumour suppressor and oncogenic activities. Thus pharmacological agents are needed to help elucidate ErbB4 functions. However, limitations of existing ErbB4 agonists and antagonists have led us to seek novel ErbB4 antagonists. The Q43L mutant of the ErbB4 agonist NRG2β (neuregulin 2β) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2β/Q43L may be an ErbB4 antagonist. NRG2β/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2β/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2β. In addition, NRG2β stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2β stimulates greater Akt phosphorylation than does NRG2β/Q43L. Moreover, EGFR [EGF (epidermal growth factor) receptor] kinase activity (but not that of ErbB4) is critical for coupling ErbB4 to proliferation. Experiments utilizing ErbB4 splicing isoforms and mutants suggest that NRG2β and NRG2β/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2β/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2β/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2β/Q43L and other antagonistic ligands stimulate ErbB tyrosine phosphorylation on a set of residues distinct from that stimulated by agonists, thus suggesting a novel mechanism of ErbB receptor regulation. Moreover, NRG2β/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics.

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Section: Resultsmentioning

confidence: 99%

The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist

Wilson

Mill

Gallo

et al. 2012

Biochemical Journal

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“…All other chemicals used were of reagent grade and were purchased from Sigma-Aldrich Japan (Tokyo, Japan), Nacalai Tesque (Kyoto, Japan), Wako Pure Chemical Industries (Osaka, Japan) or Tokyo Chemical Industry (Tokyo, Japan). 4-(3 0 -Iodoanilino)-6,7-diethoxyquinazoline was prepared by the method of Van Brocklin et al [22].…”

Section: Methodsmentioning

confidence: 99%

“…As 4-(3-iodoanilino)-6,7-diethoxyquinazoline was reported to possess more potent biological activity than the corresponding 6,7-dimethoxy derivative [22,23], we synthesized and evaluated radioiodinated 4-(3-iodoanilino)-6,7-diethoxyquinazoline (m-IPQ) for EGFR-TK imaging.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of radioiodinated quinazoline derivative as a new ligand for EGF receptor tyrosine kinase activity using SPECT

et al. 2010

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[(125)I]m-IPQ showed a relatively high tumor accumulation with selective EGFR-TK binding. Moreover, the tumor uptake of [(125)I]m-IPQ might be reflected in the amount of EGFR-TK expression in the tumor. These good characteristics of [(125)I]m-IPQ suggested that a ¹²³I-labeled counterpart, [¹²³I]m-IPQ, would have great potential for EGFR-TK imaging with SPECT. However, the in vivo stability of this compound needs to improve.

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“…This molecule functions by inhibiting ATP binding to the tyrosine kinase domain (59). It exhibits approximately 50-fold selectivity for the EGFR over ErbB2 and approximately 20-fold selectivity for the EGFR over ErbB4 (60). PD153035 was added to cells for 3 or 6 hours, while control cells were treated with media containing 0.01% DMSO (vehicle).…”

Section: Methodsmentioning

confidence: 99%

Reconstitution of Amphiregulin–Epidermal Growth Factor Receptor Signaling in Lung Squamous Cell Carcinomas Activates PTHrP Gene Expression and Contributes to Cancer-Mediated Diseases of the Bone

Gilmore

Gonterman

Menon

et al. 2009

Molecular Cancer Research

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Parathyroid hormone-related protein (PTHrP) is the causative factor of the paraneoplastic syndrome humoral hypercalcemia of malignancy (HHM) and it also contributes to osteolytic metastases, both of which are common complications of squamous carcinomas of the lung. Inhibition of autocrine epidermal growth factor receptor (EGFR) signaling has been shown to reduce plasma calcium and PTHrP concentrations in two lung squamous cell carcinoma xenograft models of HHM. The purpose of this study was to investigate the mechanism by which EGFR is activated and stimulates PTHrP gene expression in lung squamous carcinoma cell lines. Amphiregulin (AREG) was the only EGFR ligand that could be consistently detected in conditioned media from the SCC lines, and reduction of its expression either by siRNA or by precipitating antibody reduced PTHrP mRNA expression as effectively as EGFR-targeted inhibition. Using siRNA knockdown or inhibitors to upstream regulators of AREG shedding including TACE, Src/Lck, and G i/o , also reduced PTHrP mRNA expression. We determined that blockade of autocrine AREG-EGFR signaling does not affect PTHrP mRNA stability. Of the three PTHrP promoters (P1, P2, and P3), P1 mRNA could be reduced by nearly 100% with an EGFR inhibitor, and both epidermal growth factor and AREG stimulated P1 mRNA by ∼5-fold. Finally, ectopic expression of EGFR in a receptor-low but AREG-expressing cell line increased PTHrP mRNA levels in vitro, and induced the capability to cause HHM and rapid osteolytic growth in vivo. Taken together, we provide evidence that AREG stimulation of EGFR results in high levels of PTHrP gene expression, contributing to cancer-associated bone pathology.

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Anilinodialkoxyquinazolines: Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

Abstract: The epidermal growth factor receptor (EGFR), a long-standing drug development target, is also a desirable target for imaging. 2

Cited by 31 publications

References 54 publications

The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist

The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist

Evaluation of radioiodinated quinazoline derivative as a new ligand for EGF receptor tyrosine kinase activity using SPECT

Reconstitution of Amphiregulin–Epidermal Growth Factor Receptor Signaling in Lung Squamous Cell Carcinomas Activates PTHrP Gene Expression and Contributes to Cancer-Mediated Diseases of the Bone

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