BMS-754807
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MedKoo CAT#: 200534

CAS#: 1001350-96-4

Description: BMS-754807 is an orally bioavailable antagonist of human insulin-like growth factor type I receptor (IGF-1R) with potential antineoplastic activity. IGF-1R antagonist BMS-7548077 binds to IGF-1R, preventing IGF-1 ligand binding and activation of IGF-1R-mediated signaling pathways; inhibition of IGF-1R-mediated signaling pathways may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. IGF-1R is a receptor tyrosine kinase expressed on most tumor cells and is involved in mitogenesis, angiogenesis, and tumor cell survival.


Chemical Structure

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BMS-754807
CAS# 1001350-96-4

Theoretical Analysis

MedKoo Cat#: 200534
Name: BMS-754807
CAS#: 1001350-96-4
Chemical Formula: C23H24FN9O
Exact Mass: 461.20878
Molecular Weight: 461.49
Elemental Analysis: C, 59.86; H, 5.24; F, 4.12; N, 27.32; O, 3.47

Price and Availability

Size Price Availability Quantity
50.0mg USD 450.0 2 weeks
100.0mg USD 750.0 2 weeks
200.0mg USD 950.0 2 weeks
500.0mg USD 2150.0 2 weeks
1.0g USD 3850.0 2 weeks
2.0g USD 5850.0 2 weeks
5.0g USD 9850.0 2 weeks
Bulk inquiry

Synonym: BMS754807; BMS-754807; BMS 754807.

IUPAC/Chemical Name: (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.

InChi Key: LQVXSNNAFNGRAH-QHCPKHFHSA-N

InChi Code: InChI=1S/C23H24FN9O/c1-23(21(34)26-15-7-8-18(24)25-13-15)9-3-10-32(23)22-28-20(17-4-2-11-33(17)31-22)27-19-12-16(29-30-19)14-5-6-14/h2,4,7-8,11-14H,3,5-6,9-10H2,1H3,(H,26,34)(H2,27,28,29,30,31)/t23-/m0/s1

SMILES Code: O=C([C@@]1(C)N(C(N=C2NC3=NNC(C4CC4)=C3)=NN5C2=CC=C5)CCC1)NC6=CC=C(F)N=C6

Appearance: solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: BMS-754807 is a potent and reversible IGF-1R/IR inhibitor (IC50=1.8 and 1.7 nM, respectively; Ki=<2 nM for both).
In vitro activity: The results shown in Figure 2 illustrate that the decrease in the percentage of viable cells after treatment with 10 µM BMS (BMS754807) or OSI in different glioblastoma, colon and pancreatic carcinoma cell lines was quite different for the two inhibitors, with the result that BMS had a stronger inhibitory effect on cell growth in almost all cell lines tested as compared with OSI. Indeed, several cell lines were resistant to OSI but were inhibited by BMS, which was especially evident for the three glioblastoma primary cultures and the IMIM-PC-2 pancreatic carcinoma cell line. In general, 10 µM OSI inhibited cell growth by 10–40%, whereas the same concentration of BMS caused a 40–80% inhibition, depending on the cell line. Reference: Cancers (Basel). 2020 Dec; 12(12): 3717. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763458/
In vivo activity: BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Reference: Mol Cancer Ther. 2009 Dec;8(12):3341-9. https://pubmed.ncbi.nlm.nih.gov/19996272/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 74.0 160.35
DMF 30.0 65.01
Ethanol 61.0 132.18
Ethanol:PBS (pH 7.2) (1:1) 0.5 1.08

Preparing Stock Solutions

The following data is based on the product molecular weight 461.49 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Fuentes-Baile M, Ventero MP, Encinar JA, García-Morales P, Poveda-Deltell M, Pérez-Valenciano E, Barberá VM, Gallego-Plazas J, Rodríguez-Lescure Á, Martín-Nieto J, Saceda M. Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines. Cancers (Basel). 2020 Dec 11;12(12):3717. doi: 10.3390/cancers12123717. PMID: 33322337; PMCID: PMC7763458. 2. Xue L, Chen F, Yue F, Camacho L, Kothapalli S, Wei G, Huang S, Mo Q, Ma F, Li Y, Jiralerspong S. Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer. Breast Cancer Res Treat. 2021 Jan;185(1):73-84. doi: 10.1007/s10549-020-05927-5. Epub 2020 Sep 17. PMID: 32940848; PMCID: PMC7855212. 3. Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S, Cao C, Cantor GH, Dell-John J, Chen C, Discenza L, Menard K, Li A, Trainor G, Vyas D, Kramer R, Attar RM, Gottardis MM. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009 Dec;8(12):3341-9. doi: 10.1158/1535-7163.MCT-09-0499. PMID: 19996272.
In vitro protocol: 1. Fuentes-Baile M, Ventero MP, Encinar JA, García-Morales P, Poveda-Deltell M, Pérez-Valenciano E, Barberá VM, Gallego-Plazas J, Rodríguez-Lescure Á, Martín-Nieto J, Saceda M. Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines. Cancers (Basel). 2020 Dec 11;12(12):3717. doi: 10.3390/cancers12123717. PMID: 33322337; PMCID: PMC7763458. 2. Xue L, Chen F, Yue F, Camacho L, Kothapalli S, Wei G, Huang S, Mo Q, Ma F, Li Y, Jiralerspong S. Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer. Breast Cancer Res Treat. 2021 Jan;185(1):73-84. doi: 10.1007/s10549-020-05927-5. Epub 2020 Sep 17. PMID: 32940848; PMCID: PMC7855212.
In vivo protocol: 1. Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S, Cao C, Cantor GH, Dell-John J, Chen C, Discenza L, Menard K, Li A, Trainor G, Vyas D, Kramer R, Attar RM, Gottardis MM. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009 Dec;8(12):3341-9. doi: 10.1158/1535-7163.MCT-09-0499. PMID: 19996272.

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1: Majo VJ, Arango V, Simpson NR, Prabhakaran J, Kassir SA, Underwood MD, Bakalian M, Canoll P, John Mann J, Dileep Kumar JS. Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R. Bioorg Med Chem Lett. 2013 Jul 15;23(14):4191-4. doi: 10.1016/j.bmcl.2013.05.026. Epub 2013 May 16. PubMed PMID: 23743281.

2: Awasthi N, Zhang C, Ruan W, Schwarz MA, Schwarz RE. BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor, enhances gemcitabine response in pancreatic cancer. Mol Cancer Ther. 2012 Dec;11(12):2644-53. doi: 10.1158/1535-7163.MCT-12-0447. Epub 2012 Oct 9. PubMed PMID: 23047891.

3: Lee SJ, Kim EJ, Lee HJ, Kim SY, Oh SJ, Ryu JS, Moon DH, Ahn JH, Kim SW. A pilot study for the early assessment of the effects of BMS-754807 plus gefitinib in an H292 tumor model by [(18)F]fluorothymidine-positron emission tomography. Invest New Drugs. 2013 Jun;31(3):506-15. doi: 10.1007/s10637-012-9874-y. Epub 2012 Sep 18. PubMed PMID: 22987020.

4: Hou X, Huang F, Macedo LF, Harrington SC, Reeves KA, Greer A, Finckenstein FG, Brodie A, Gottardis MM, Carboni JM, Haluska P. Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer. Cancer Res. 2011 Dec 15;71(24):7597-607. doi: 10.1158/0008-5472.CAN-11-1080. Epub 2011 Oct 31. PubMed PMID: 22042792; PubMed Central PMCID: PMC4004036.

5: Kolb EA, Gorlick R, Lock R, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups C, Smith MA, Houghton PJ. Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2011 Apr;56(4):595-603. doi: 10.1002/pbc.22741. Epub 2010 Dec 22. PubMed PMID: 21298745.

6: Huang F, Hurlburt W, Greer A, Reeves KA, Hillerman S, Chang H, Fargnoli J, Graf Finckenstein F, Gottardis MM, Carboni JM. Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res. 2010 Sep 15;70(18):7221-31. doi: 10.1158/0008-5472.CAN-10-0391. Epub 2010 Aug 31. PubMed PMID: 20807811.

7: Dinchuk JE, Cao C, Huang F, Reeves KA, Wang J, Myers F, Cantor GH, Zhou X, Attar RM, Gottardis M, Carboni JM. Insulin receptor (IR) pathway hyperactivity in IGF-IR null cells and suppression of downstream growth signaling using the dual IGF-IR/IR inhibitor, BMS-754807. Endocrinology. 2010 Sep;151(9):4123-32. doi: 10.1210/en.2010-0032. Epub 2010 Jul 7. PubMed PMID: 20610571.

8: Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S, Cao C, Cantor GH, Dell-John J, Chen C, Discenza L, Menard K, Li A, Trainor G, Vyas D, Kramer R, Attar RM, Gottardis MM. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009 Dec;8(12):3341-9. doi: 10.1158/1535-7163.MCT-09-0499. Epub . PubMed PMID: 19996272.

9: Wittman MD, Carboni JM, Yang Z, Lee FY, Antman M, Attar R, Balimane P, Chang C, Chen C, Discenza L, Frennesson D, Gottardis MM, Greer A, Hurlburt W, Johnson W, Langley DR, Li A, Li J, Liu P, Mastalerz H, Mathur A, Menard K, Patel K, Sack J, Sang X, Saulnier M, Smith D, Stefanski K, Trainor G, Velaparthi U, Zhang G, Zimmermann K, Vyas DM. Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J Med Chem. 2009 Dec 10;52(23):7360-3. doi: 10.1021/jm900786r. PubMed PMID: 19778024.



Additional Information

BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings. (source: Cancer Res. 2011 Dec 15;71(24):7597-607. )