Tyrosine Kinase Inhibitors. 17. Irreversible Inhibitors of the Epidermal Growth Factor Receptor:  4-(Phenylamino)quinazoline- and 4-(Phenylamino)pyrido[3,2-<i>d</i>]pyrimidine-6-acrylamides Bearing Additional Solubilizing Functions.

Smaill, Jeff B.; Rewcastle, Gordon W.; Bridges, Alexander J.; Zhou, Hairong; Showalter, H. D. Hollis; Fry, David W.; Nelson, James M.; Sherwood, Veronika; Elliott, William L.; Vincent, Patrick W.; DeJohn, Dana E.; Loo, Joseph A.; Greis, Kenneth D.; Chan, Onyee; Reyner, Eric L.; Lipka, Elke; Denny, William A.

doi:10.1021/jm000250q

Cited by 43 publications

(68 citation statements)

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“…We used CI-1033, which is a pan-HER inhibitor shown to inhibit members of HER family receptors in cell culture models (24). Treatment of PC-3 cells with different concentrations of CI-1033 showed that cell proliferation was not altered at 1 Amol/L concentration for 24 hours (Fig.…”

Section: Pc-3 Cells Use Growth Factor Receptor Signaling For Cxcl12-mmentioning

confidence: 99%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

120

102

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Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient -human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft -disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4 -induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.

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Section: Pc-3 Cells Use Growth Factor Receptor Signaling For Cxcl12-mmentioning

confidence: 99%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

120

102

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“…To investigate the dependence of YB-1-transduced cells on EGFR-activated signaling for proliferation in SFH medium, we performed growth assays in the presence of 0.1 or 1 mM CI-1033, a kinase inhibitor specific for the ErbB family (Fry et al, 1998;Smaill et al, 2000). This inhibitor was slightly less potent in reducing the proliferation of H16-YB-1 cells compared to amphiregulin-overexpressing H16-AR cells ( Figure 6).…”

Section: Erbb Kinase Activity Is Required For Egf Independence In Yb-mentioning

confidence: 99%

Y-box-binding protein 1 confers EGF independence to human mammary epithelial cells

et al. 2005

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The epidermal growth factor receptor (EGFR) is linked to poor outcome in breast cancer, and resistance to hormonal therapy is often accompanied by activation of growth factor receptors. To investigate the mechanism(s) by which EGFR becomes activated in breast cancer, we screened a cDNA expression library for genes that mediate EGF-independent proliferation of human mammary epithelial cells (HMECs). We isolated the NSEP1 cDNA encoding Y-box-binding protein 1 (YB-1), a multifunctional transcriptional and translational regulator. This cDNA conferred growth factor independence to HMECs. YB-1-transduced cells overexpressed EGFR, but ErbB-2 (Her-2/neu) levels were unchanged. Moreover, EGFR was constitutively phosphorylated in the absence of exogenous ligand. In these cells, an EGFR-blocking antibody failed to inhibit proliferation, conditioned medium activity could not be detected, and the synthesis of EGFR ligands was reduced compared to parental cells. This suggests that EGFR is activated in a ligandindependent fashion. However, cell growth could be blocked with an ErbB kinase inhibitor, indicating that EGFR signaling plays a major role in YB-1-induced growth factor independence. Taken together, our results demonstrate that YB-1 overexpression can induce EGF independence in HMECs via activation of the EGFR pathway. This could represent one of the mechanisms by which YB-1 contributes to breast tumor aggressiveness.

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“…The significant lack of CI-1033 excreted in urine indicates elimination to be primarily metabolic. Preclinical studies indicate significant metabolism of CI-1033 in animal models and in animal and human liver microsomes, with the primary route being glutathione conjugation at the reactive site (49 Table 5. Median (minimum-maximum) CI-1033 plasma concentration (ng/mL) summarized by dose (N = 22) (49).…”

Section: Number Of Patients (%)mentioning

confidence: 99%

Phase 1 Clinical and Pharmacokinetics Evaluation of Oral CI-1033 in Patients with Refractory Cancer

Nemunaitis

Eiseman

Cunningham

et al. 2005

Clinical Cancer Research

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Purpose:To determine the tolerability and pharmacokinetics of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, administered over 14 consecutive days of a 21-day cycle. Design: Phase 1, multicenter trial involving patients with solid tumors that are refractory to standard therapy. CI-1033 was administered initially at 300 mg/day to a minimum cohort of three patients. Dose escalation proceeded at V40% increments. Patients were evaluated for toxicity, pharmacokinetic profile, and evidence of response. Results: Thirty-two patients entered the trial and were evaluable for safety assessment. Doselimiting toxicity (diarrhea, rash, and/or anorexia) occurred at the 560 mg dose level; the maximum tolerated dose was 450 mg. No patients achieved objective responses and six patients achieved stable disease. Plasma CI-1033 concentrations increased with increasing dose. CI-1033 was not eliminated in urine to any appreciable extent. Conclusions: CI-1033 is suitable for phase 2 testing at the 450 mg/day dose level when administered for 14 days in a 21-day cycle. The pharmacokinetic profile is consistent with biologically relevant plasma concentrations over the dosing interval.CI-1033, an orally available 4-anilinoquinazoline derivative, is a highly potent and selective pan-erbB tyrosine kinase inhibitor that irreversibly blocks intracellular signaling through all members of the erbB receptor family [erbB-1 (epidermal growth factor receptor, EGFR), erbB-2 (HER-2/neu), erbB-3, erbB-4, and the erbB-1 truncate, EGFR vIII; refs. (1 -3)]. The erbB family of tyrosine-specific protein kinases is involved in the regulation of many malignant cell functions, including proliferation, differentiation, survival, induction of angiogenesis, metastatic spread, and resistance to chemotherapy and radiotherapy (4,5). Over 90% of all solid tumors express at least one member of the erbB receptor family (6 -8) and erbB receptor/ligand overexpression correlates with poor prognosis and reduced survival in patients with a variety of cancers including breast cancer, melanoma, and head and neck cancer (3, 9 -15). In vitro work also shows that overexpression of two or more erbB family members has been correlated with a further worsening of prognosis (16 -20).Numerous anticancer therapeutic approaches to blocking signal transduction through erbB-mediated pathways have been attempted, including antibodies targeting the erbB extracellular domain, small molecule tyrosine kinase inhibitors specifically targeting one or more erbB family members, antisense oligonucleotides, ligand-linked toxins, and immunotoxin conjugates (21 -25). Trastuzumab (Herceptin), a monoclonal antibody that specifically targets the erbB-2 extracellular domain, was the first effective clinical translation of this approach and is approved for the treatment of erbB-2 overexpressing metastatic breast cancer-as second-line monotherapy and as first-line therapy when combined with paclitaxel (26 -31). More recently, an erbB-1-specific monoclonal antibody, cetuximab (Erbitux, IMC-C225...

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Tyrosine Kinase Inhibitors. 17. Irreversible Inhibitors of the Epidermal Growth Factor Receptor: 4-(Phenylamino)quinazoline- and 4-(Phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides Bearing Additional Solubilizing Functions.

Cited by 43 publications

References 0 publications

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Y-box-binding protein 1 confers EGF independence to human mammary epithelial cells

Phase 1 Clinical and Pharmacokinetics Evaluation of Oral CI-1033 in Patients with Refractory Cancer

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