RO4383596, an orally active KDR, FGFR, and PDGFR inhibitor: Synthesis and biological evaluation

McDermott, Lee A.; Simcox, Mary Ellen; Higgins, Brian; Nevins, Tom; Kolinsky, Kenneth; Smith, Melissa; Yang, Hong; Li, Jia K.; Chen, Yingsi; Ke, June; Mallalieu, Navita L.; Egan, Tom; Kolis, Stan; Railkar, Aruna; Gerber, Louise; Luk, Kin-chun

doi:10.1016/j.bmc.2005.05.012

Cited by 22 publications

(14 citation statements)

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“…As a distinct means to test if the FGF2 and FGFRs constitute a signal pathway contributing to HNSCC growth and transformation, cells were treated with increasing concentrations of the FGFR inhibitor, RO4383596 (18, 36), or an EGFR specific inhibitor, AG1478, and submitted to immunoblot analyses for basal ERK phosphorylation as a measure of proximal RTK signaling. As shown in Figure 4, CCL30 and 584-A2 responded to RO4383596 with a complete, dose-dependent inhibition of basal ERK phosphorylation while Detroit562 cells exhibited partial reduction of phospho-ERK levels.…”

Section: Resultsmentioning

confidence: 99%

Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

Marshall

Hinz

Kono

et al. 2011

Clinical Cancer Research

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Purpose We previously reported that a fibroblast growth factor (FGF) receptor (FGFR) signaling pathway drives growth of lung cancer cell lines of squamous and large cell histologies. Herein, we explored FGFR dependency in cell lines derived from the tobacco-related malignancy, head and neck squamous cell carcinoma (HNSCC). Experimental Design FGF and FGFR mRNA and protein expression was assessed in nine HNSCC cell lines. Dependence on secreted FGF2 for cell growth was tested with FP-1039, an FGFR1-Fc fusion protein. FGFR and EGFR-dependence was defined by sensitivity to multiple inhibitors selective for FGFRs or EGFR. Results FGF2 was expressed in eight of the nine HNSCC cell lines examined. Also, FGFR2 and FGFR3 were frequently expressed while only two lines expressed FGFR1. FP-1039 inhibited growth of HNSCC cell lines expressing FGF2, identifying FGF2 as an autocrine growth factor. FGFR inhibitors selectively reduced in vitro growth and ERK signaling in three HNSCC cell lines while three distinct lines exhibited responsiveness to both EGFR and FGFR inhibitors. Combinations of these drugs yielded additive growth inhibition. Finally, three cell lines were highly sensitive to EGFR TKIs with no contribution from FGFR pathways. Conclusions FGFR signaling was dominant or co-dominant with EGFR in six HNSCC lines while three lines exhibited little or no role for FGFRs and were highly EGFR-dependent. Thus, the HNSCC cell lines can be divided into subsets defined by sensitivity to EGFR and FGFR-specific TKIs. FGFR inhibitors may represent novel therapeutics to deploy alone or in combination with EGFR inhibitors in HNSCC.

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Section: Resultsmentioning

confidence: 99%

Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

Marshall

Hinz

Kono

et al. 2011

Clinical Cancer Research

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“…While untreated H322c or H1650 cells show little or no increase in ERK activation when stimulated with FGF2 (1.5±0.2, 0.9±0.2 fold, respectively) or FGF7 (1.2±0.1, 0.6±0.2 fold, respectively) (Figure 3A lanes 2 and 3), cells cultured 72 hrs in the presence of AG1478 to induce FGFR2 and FGFR3 have significantly lower basal ERK activity (0.4±0.1, 0.2±0.1 fold, respectively) due to blockade of the EGFR pathway, (Figure 3A lane 7) but a marked increase in ERK phosphorylation in response to FGF2 (5.0±1.2, 10.7±4.2 fold, respectively) and FGF7 (6.4±1.0, 8.9±5.7 fold, respectively) (Figure 3A lanes 8 and 9). To define that ERK activation after AG1478 treatment is FGFR mediated, cells cultured for 3 days in the presence of AG1478 were pre-incubated with an FGFR TKI, RO4383596 [11], [23], 1 hr prior to FGF2 or FGF7 stimulation. This treatment with RO4383596 completely eliminated the FGF stimulated phospho-ERK response following AG1478 treatment (Figure 3A lanes 11 and 12), but has no effect on phospho-ERK when used alone (Figure 3A lanes 4, 5, and 6).…”

Section: Resultsmentioning

confidence: 99%

Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression

et al. 2010

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Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5′ flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors.

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“…In cell assays, it potently inhibits VEGF-stimulated HUVEC proliferation (IC 50 = 68 nM), while in vivo, oral administration at a dose of 25 mg/kg twice a day yields a good pharmacokinetic profile and leads to 81% inhibition of corneal angiogenesis in a mouse corneal pocket assay [153]. Compound (62b) RO4396686, recently published by the same authors, shows a biological behaviour similar to (62a) and significantly inhibits tumor growth at doses as low as 50 mg/kg [154] as tested in an H460a xenograft tumor model.…”

Section: Pyrimido-pyrimidinonesmentioning

confidence: 99%

Antiangiogenic Agents: an Update on Small Molecule VEGFR Inhibitors

Schenone¹,

Bondavalli²,

Botta

2007

CMC

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Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiological conditions or under pathological situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signalling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small molecule VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, especially from a biological point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chemistry in terms of chemical structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased number of tyrosine kinase inhibitors in the most recent literature reports; their biological profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.

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RO4383596, an orally active KDR, FGFR, and PDGFR inhibitor: Synthesis and biological evaluation

Cited by 22 publications

References 14 publications

Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

Fibroblast Growth Factor Receptors Are Components of Autocrine Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells

Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression

Antiangiogenic Agents: an Update on Small Molecule VEGFR Inhibitors

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