Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

Renhowe, Paul A.; Pecchi, Sabina; Shafer, Cynthia M.; Machajewski, Timothy; Jazan, Elisa M.; Taylor, Clarke; Antonios-McCrea, William; McBride, Christopher M.; Frazier, Kelly; Wiesmann, Marion; Lapointe, Gena; Feucht, Paul; Warne, Robert; Heise, Carla; Menezes, Daniel Francisco Nagão; Aardalen, Kimberly; Ye, Helen; He, M.M.; Le, Vincent; Vora, Jayesh; Jansen, Johanna M.; Wernette-Hammond, M E; Harris, Andrea

doi:10.1021/jm800790t

Cited by 129 publications

(78 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…20 The inhibitory effect of Dovitinib on PDGFR was detected in MDA-MB-231 cells by checking the change of PDGFß mRNA expression after treatment. PDGFß mRNA expression level was enhanced by 2-fold when MDA-MB-231 cells were cultured with CAFs-conditioned media.…”

Section: Resultsmentioning

confidence: 99%

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

et al. 2015

View full text Add to dashboard Cite

A constitutive and dynamic interaction between tumor cells and their surrounding stroma is a prerequisite for tumor invasion and metastasis. Fibroblasts and myofibroblasts (collectively called cancer associated fibroblasts, CAFs) often represent the major cellular components of tumor stroma. Tumor cells secret different growth factors which induce CAFs proliferation and differentiation, and, consequently, CAFs secrete different chemokines, cytokines or growth factors which induce tumor cell invasion and metastasis. In this study we showed here that CAFs from breast cancer surgical specimens significantly induced the invasion of breast cancer cells in vitro. Most interestingly, the novel multiple tyrosine kinase inhibitor Dovitinib significantly blocked the CAFs-induced invasion of breast cancer cells by, at least in part, inhibition of the expression and secretion of CCL2, CCL5 and VEGF in CAFs. Inhibition of PI3K/Akt/mTOR signaling could be responsible for the effects of Dovitinib, since Dovitinib antagonized the promoted phosphorylated Akt after treatment with PDGF, FGF or breast cancer cell-conditioned media. Treatment with Dovitinib in combination with PI3K/Akt/mTOR signaling inhibitors Ly294002 or RAD001 resulted in additive inhibition of cell invasion. This is the first in vitro study to show that the multiple tyrosine kinase inhibitor has therapeutic activities against breast cancer metastasis by targeting both tumor cells and CAFs.

show abstract

Section: Resultsmentioning

confidence: 99%

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Dovitinib is a small-molecule inhibitor of multiple receptor tyrosine kinases (RTK), including fibroblast growth factor receptor (FGFR), VEGFR, c-KIT, and FMS-like tyrosine kinase 3 (FLT3; ref. 4). According to previous studies, dovitinib exhibits potent tumor growth inhibition in a board range of preclinical animal models.…”

Section: Introductionmentioning

confidence: 96%

Dovitinib Induces Apoptosis and Overcomes Sorafenib Resistance in Hepatocellular Carcinoma through SHP-1–Mediated Inhibition of STAT3

Tai

Cheng

Shiau

et al. 2012

Molecular Cancer Therapeutics

117

114

View full text Add to dashboard Cite

The multiple kinase inhibitor dovitinib is currently under clinical investigation for hepatocellular carcinoma (HCC). Here, we investigated the mechanistic basis for the effects of dovitinib in HCCs. Dovitinib showed significant antitumor activity in HCC cell lines PLC5, Hep3B, Sk-Hep1, and Huh-7. Dovitinib downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 and subsequently reduced the levels of expression of STAT3-related proteins Mcl-1, survivin, and cyclin D1 in a time-dependent manner. Ectopic expression of STAT3 abolished the apoptotic effect of dovitinib, indicating that STAT3 is indispensable in mediating the effect of dovitinib in HCC. SHP-1 inhibitor reversed downregulation of p-STAT3 and apoptosis induced by dovitinib, and silencing of SHP-1 by RNA interference abolished the effects of dovitinib on p-STAT3, indicating that SHP-1, a protein tyrosine phosphatase, mediates the effects of dovitinib. Notably, dovitinib increased SHP-1 activity in HCC cells. Incubation of dovitinib with pure SHP-1 protein enhanced its phosphatase activity, indicating that dovitinib upregulates the activity of SHP-1 via direct interactions. In addition, dovitinib induced apoptosis in two sorafenib-resistant cell lines through inhibition of STAT3, and sorafenib-resistant cells showed significant activation of STAT3, suggesting that targeting STAT3 may be a useful approach to overcome drug resistance in HCC. Finally, in vivo, dovitinib significantly suppressed growth of both Huh-7 and PLC5 xenograft tumors and downregulated p-STAT3 by increasing SHP-1 activity. In conclusion, dovitinib induces significant apoptosis in HCC cells and sorafenib-resistant cells via SHP-1-mediated inhibition of STAT3. Mol Cancer Ther; 11(2); 452-63. Ó2011 AACR.

show abstract

“…According to previous studies, dovitinib exhibits potent tumorgrowth inhibition in a broad range of preclinical animal models. For example, dovitinib specifically inhibited proliferation of primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome (17). In addition, dovitinib induces apoptosis in FGFR-expression hepatocellular carcinoma cells and in mammary cells via inhibition of PI3K/AKT signaling pathway (18).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

Eritja

Domingo

Dosil

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Mutations in fibroblast growth factor receptor 2 (FGFR2) have been recently described as a molecularspecific feature in endometrial carcinomas and the presence of activated FGFR2 mutations is associated with poor prognosis. For that reason, inhibition of FGFR2 could be a therapeutic target in the treatment of endometriod carcinomas. In this work, we investigated the antitumoral activity of dovitinib (a multiple kinase inhibitor) in human endometrial cancer cell (ECC) lines. We found that dovitinib caused cell growth arrest, loss of clonogenic growth, and cell-cycle arrest in FGFR2-mutated ECCs in in vitro and in vivo experiments. Next, we investigated the mechanistic basis of dovitinib effects. We could determine that dovitinib modified expression levels of well-known key cell-cycle regulatory proteins that induce cellular senescence. To further investigate the role of dovitinib, we analyzed its effect on estrogen receptor a (ER-a) expression. Surprisingly, we discovered that dovitinib enhances ER-a expression in FGFR2-mutant ECCs. Because blocking one signaling pathway is often not sufficient to cause total tumor regression and the effectiveness of individual inhibitors is often short-lived, we examined the impact of targeting FGFR2 with dovitinib in combination with a selective ER antagonist, fulvestrant (ICI182.780). Combination of dovitinib plus ICI182.780 resulted in a significantly higher inhibition of cell growth than dovitinib treatment alone. These findings suggest that combinatory therapies using dovitinib plus ICI182.780 treatment can be truly effective in patients with endometrial carcinomas carrying FGFR2 mutations. Mol Cancer Ther; 13(4); 776-87. Ó2014 AACR.

show abstract

Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

Cited by 129 publications

References 34 publications

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

Dovitinib Induces Apoptosis and Overcomes Sorafenib Resistance in Hepatocellular Carcinoma through SHP-1–Mediated Inhibition of STAT3

Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

Contact Info

Product

Resources

About