BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Carboni, Joan M.; Wittman, Mark D.; Yang, Zheng; Lee, Francis; Greer, Ann; Hurlburt, Warren; Hillerman, Stephen; Cao, Carolyn; Cantor, Glenn H.; Dell-John, Janet; Chen, Cliff; Discenza, Lorell; Menard, Krista; Li, Aixin; Trainor, George L.; Vyas, Dolatrai M.; Kramer, Robert A.; Attar, Ricardo M.; Gottardis, Marco M.

doi:10.1158/1535-7163.mct-09-0499

Cited by 240 publications

(236 citation statements)

References 41 publications

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“…In our studies, there was no apparent in vivo toxicity during a 2-week treatment course, however, toxicity for long-term inhibition of the IGF-1R and IR functions remains to be elucidated. A previous study reported only a short-term increase in serum glucose or insulin levels at doses up to 12.5 mg/kg, with an average weight change of −1.5 grams at 25 mg/kg, but no mortality [33]. In our study, no significant change in mouse body weight was observed by BMS-754807 therapy, but blood glucose measurements were not obtained.…”

Section: Discussioncontrasting

confidence: 60%

“…The IGF signaling inhibitor BMS-754807 has shown antitumor activity in multiple tumor models including epithelial, mesenchymal and hematopoietic cancer cells [33]. We observed the effect of BMS-754807 in subcutaneous xenografts using two aggressive PDAC cell lines, AsPC-1 and Panc-1.…”

Section: Discussionmentioning

confidence: 99%

“…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]. Recently, predictive biomarkers, including overexpression of IGF-1R, and KRAS and BRAF mutation status have been delineated for effectiveness of BMS-754807 [37].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…After 48 h, the pAkt signal was observed in clustered and likely newly divided cells (Figure 3c, see insert). To test whether this Ca 2 þ deficiency-induced Akt activation is downstream of the IGF1R, two structurally distinct IGF1R inhibitors, BMS-754807 19 and NVP-AEW541 20 were used. Blockage of the IGF1R-mediated signaling abolished pAkt signal under low [Ca 2 þ ] (Figures 3d and e).…”

Section: Resultsmentioning

confidence: 99%

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

et al. 2013

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Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca 2 þ deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca 2 þ -transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca 2 þ ] environments. BrdU pulse-labeling experiments suggest that low [Ca 2 þ ] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca 2 þ ] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca 2 þ -selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca 2 þ ]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca 2 þ ]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca 2 þ ]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca 2 þ ]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca 2 þ ]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca 2 þ ] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca 2 þ deficiency.

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“…Recombinant enzymes were purchased from Invitrogen (Carlsbad, CA, USA) or produced as described previously. 24 Keyhole limpet hemocyanin (KLH) used for immunization was purchased from Pierce (Rockford, IL, USA). SET2 cells were obtained from DSMZ (Braunschweig, Germany).…”

Section: Reagentsmentioning

confidence: 99%

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

et al. 2011

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We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F -positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2 V617F -expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

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BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Cited by 240 publications

References 41 publications

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

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

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

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