BMS-754807 - CAS 1001350-96-4
Catalog number: 1001350-96-4
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
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Targets:
IGF-1R
Description:
BMS-754807 is an orally bioavailable antagonist of human insulin-like growth factor type I receptor (IGF-1R) with potential antineoplastic activity. BMS-7548077 binds to IGF-1R, preventing IGF-1 ligand binding and activation of IGF-1R-mediated signaling pathways.
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Purity:
0.98
Appearance:
solid powder
Synonyms:
BMS754807; BMS 754807.
MSDS:
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Current Developer:
Bristol-Myers Squibb Inc
1.IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines.
Huang F1, Chang H1, Greer A2, Hillerman S2, Reeves KA2, Hurlburt W2, Cogswell J2, Patel D2, Qi Z2, Fairchild C2, Ryseck RP2, Wong TW2, Finckenstein FG2, Jackson J2, Carboni JM2. Mol Cancer Ther. 2015 Feb;14(2):620-30. doi: 10.1158/1535-7163.MCT-14-0794-T. Epub 2014 Dec 19.
Insulin-like growth factor receptor 1 (IGF-1R)-targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807. The results showed that cell lines with BRAF(V600E) or KRAS(G13D) mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6. In addition, the cell lines with KRAS mutations, those with either insulin receptor substrate 2 (IRS2) copy number gain (CNG) or higher IGF-1R expression levels, were more sensitive to the drug. Furthermore, cell lines with IRS2 CNG had higher levels of ligand-stimulated activation of IGF-1R and AKT, suggesting that these cell lines with IGF-IR signaling pathways more actively coupled to AKT signaling are more responsive to IGF-1R/IR inhibition.
2.Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R.
Majo VJ1, Arango V, Simpson NR, Prabhakaran J, Kassir SA, Underwood MD, Bakalian M, Canoll P, John Mann J, Dileep Kumar JS. Bioorg Med Chem Lett. 2013 Jul 15;23(14):4191-4. doi: 10.1016/j.bmcl.2013.05.026. Epub 2013 May 16.
Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [(18)F]TBAF in DMSO at 170°C at high radiochemical purity and specific activity (1-2Ci/μmol, N=10). The proof of concept of IGF-IR imaging with [(18)F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF-1R.
3.A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.
Halvorson KG1, Barton KL2, Schroeder K3, Misuraca KL4, Hoeman C2, Chung A2, Crabtree DM2, Cordero FJ2, Singh R2, Spasojevic I5, Berlow N6, Pal R6, Becher OJ7. PLoS One. 2015 Mar 6;10(3):e0118926. doi: 10.1371/journal.pone.0118926. eCollection 2015.
Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation.
4.BMS-754807 is cytotoxic to non-small cell lung cancer cells and enhances the effects of platinum chemotherapeutics in the human lung cancer cell line A549.
Franks SE1, Jones RA2, Briah R3, Murray P4, Moorehead RA5. BMC Res Notes. 2016 Mar 1;9(1):134. doi: 10.1186/s13104-016-1919-4.
BACKGROUND: Despite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide. The type I insulin-like growth factor receptor (IGF-IR) has emerged as a potential target for lung cancer treatment, however, clinical trials to date have provided disappointing results. Further research is needed to identify if certain patients would benefit from IGF-IR targeted therapies and the ideal approach to incorporate IGF-IR targeted agents with current therapies.
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CAS 1001350-96-4 BMS-754807

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