Discovery of a 1<i>H</i>-Benzoimidazol-2-yl)-1<i>H</i>-pyridin-2-one (BMS-536924) Inhibitor of Insulin-like Growth Factor I Receptor Kinase with in Vivo Antitumor Activity

Wittman, Mark D.; Carboni, Joan M.; Attar, Ricardo M.; Balasubramanian, Balu; Balimane, Praveen; Brassil, Patrick; Beaulieu, Françis; Chang, ChiehYing Y.; Clarke, Wendy; Dell, Janet; Eummer, Jeffrey; Frennesson, David B.; Gottardis, Marco M.; Greer, Ann; Hansel, Steven; Hurlburt, Warren; Jacobson, Bruce L.; Krishnananthan, Subramaniam; Lee, Francis Y.; Li, Aixin; Lin, Teng Nan; Liu, Peiying; Ouellet, Catherine; Sang, Xiaopeng; Saulnier, Mark G.; Stoffan, Karen; Sun, Yax; Velaparthi, Upender; Wong, Henry; Yang, Zheng; Zimmermann, Kurt; Zoeckler, Mary; Vyas, Dolatrai M.

doi:10.1021/jm050392q

Cited by 133 publications

(85 citation statements)

References 24 publications

(33 reference statements)

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“…Since IGF-IR and the IR are structurally related, highly specific IGF-IR inhibitors are necessary to prevent diabetogenic effects in patients. Published IGF-IR-selective RTK-inhibitors are tyrphostins (AG538 [100,101] , AG1024 [102] , AG1034 [102] ), cyclolignans (picr opodophyllin [103,104] ), 6-5 ring-fused compounds [105] , pyrrole derivatives (NVP-AEW541 [106,107] , NVP-ADW742 [108,109] ), PQIP [110] , BMS536924 [111] , and BMS-554417 [112] . Antitumorigenic effects of some inhibitors on HCC cells have been demonstrated.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Breuhahn¹

2008

WJG

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Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Breuhahn¹

2008

WJG

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“…BMS-754807 (Supplemental Figure S1) is a potent and reversible inhibitor of IGF-1R/IR (IC 50 1.8 nM/1.7 nM), which also has more limited activity toward other kinases including Met, Aurora A/B, TrkA/B, Ron, Flt3, Lck, MK2, PKA and PKC [32, 33]. BMS-754807 has shown antitumor activity in a broad range of tumor types and it also enhanced antitumor response of other agents [33–36].…”

Section: Introductionmentioning

confidence: 99%

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

et al. 2016

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Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and −87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.

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“…Since, as mentioned, IGF1R could not be readily co-precipitated with EN in FPLC fractions, we instead assessed effects of IGF1R kinase inhibition on EN/IRS1 complex formation. EN-transformed NIH3T3 cells were treated with BMS-536924, a chemical inhibitor that blocks both IGF1R and insulin receptor (INSR) kinase activity with nM potency (Wittman et al, 2005), and protein lysates were subjected to FPLC fractionation. Concentrations of BMS-536924 used for these studies selectively inhibit IGF1R and INSR, but not other tyrosine kinases (Wittman et al, 2005).…”

Section: En Interacts With Phosphorylated Irs1 In High Molecular Weigmentioning

confidence: 99%

“…EN-transformed NIH3T3 cells were treated with BMS-536924, a chemical inhibitor that blocks both IGF1R and insulin receptor (INSR) kinase activity with nM potency (Wittman et al, 2005), and protein lysates were subjected to FPLC fractionation. Concentrations of BMS-536924 used for these studies selectively inhibit IGF1R and INSR, but not other tyrosine kinases (Wittman et al, 2005). Although IGF1R remained in high molecular weight fractions under both conditions (Figure 3b, top panels), there was dramatic redistribution of both EN and IRS1 from high to low molecular weight fractions under BMS-536924 treatment ( Figure 3b, middle and bottom panels).…”

Section: En Interacts With Phosphorylated Irs1 In High Molecular Weigmentioning

confidence: 99%

A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation

Tognon¹,

Martin²,

Moradian

et al. 2011

Oncogene

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ETV6-NTRK3 (EN), a chimeric tyrosine kinase generated by t(12;15) translocations, is a dominantly acting oncoprotein in diverse tumor types. We previously showed that insulin-like growth factor 1 receptor (IGF1R) is essential for EN-mediated oncogenesis and that insulin receptor substrate 1 (IRS1) is constitutively tyrosine phosphorylated and bound by EN in transformed cells. Given that IRS1 is also an adapter for IGF1R, we hypothesized that IRS1 might localize EN to IGF1R at the membrane to activate phosphatidylinositol 3-kinase (PI3K)-Akt, which is critical for EN oncogenesis. In this study, we examined EN/IRS1/IGF1R complexes in detail. We find that both IRS1 and kinase active IGF1R are required for EN transformation, that tyrosine phosphorylated IRS1 is present in high molecular weight complexes with EN and IGF1R, and that EN colocalizes with IGF1R at the plasma membrane. Both IGF1R kinase activity and an intact cytoplasmic Y950 residue, the IRS1-docking site of IGF1R, are required, confirming the importance of the IGF1R/IRS1 interaction for EN oncogenesis. The dual specificity IGF1R and insulin receptor (INSR) inhibitor, BMS-536924, blocks EN transformation activity, cell survival and its interaction with IRS proteins, and induces a striking shift of EN proteins to smaller sized molecular complexes. We conclude that a tripartite complex of EN, IRS1 and IGF1R localizes EN to the membrane and that this is essential for EN-mediated transformation. These findings provide an explanation for the observed IGF1R dependency of EN transformation. Blocking IGF1R kinase activity may, therefore, provide a tractable therapeutic strategy for the many tumor types driven by the EN oncoprotein.

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Discovery of a 1H-Benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) Inhibitor of Insulin-like Growth Factor I Receptor Kinase with in Vivo Antitumor Activity

Abstract: Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.

Cited by 133 publications

References 24 publications

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation

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