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
25.0mg USD 350.0 2 weeks
50.0mg USD 550.0 2 weeks
100.0mg USD 950.0 2 weeks
200.0mg USD 1650.0 2 weeks
500.0mg USD 3250.0 2 weeks
1.0g USD 4650.0 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: Hebron KE, Wan X, Roth JS, Liewehr DJ, Sealover NE, Frye WJE, Kim A, Stauffer S, Perkins OL, Sun W, Isanogle KA, Robinson CM, James A, Awasthi P, Shankarappa P, Luo X, Lei H, Butcher D, Smith R, Edmondson EF, Chen JQ, Kedei N, Peer CJ, Shern JF, Figg WD, Chen L, Hall MD, Difilippantonio S, Barr FG, Kortum RL, Robey RW, Vaseva AV, Khan J, Yohe ME. The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models. Clin Cancer Res. 2023 Jan 17;29(2):472-487. doi: 10.1158/1078-0432.CCR-22-1646. PMID: 36322002; PMCID: PMC9852065.

2: Cyra M, Schulte M, Berthold R, Heinst L, Jansen EP, Grünewald I, Elges S, Larsson O, Schliemann C, Steinestel K, Hafner S, Simmet T, Wardelmann E, Kailayangiri S, Rossig C, Isfort I, Trautmann M, Hartmann W. SS18-SSX drives CREB activation in synovial sarcoma. Cell Oncol (Dordr). 2022 Jun;45(3):399-413. doi: 10.1007/s13402-022-00673-w. Epub 2022 May 12. PMID: 35556229; PMCID: PMC9187574.

3: Eke I, Aryankalayil MJ, Bylicky MA, Makinde AY, Liotta L, Calvert V, Petricoin EF, Graves EE, Coleman CN. Radiotherapy alters expression of molecular targets in prostate cancer in a fractionation- and time-dependent manner. Sci Rep. 2022 Mar 3;12(1):3500. doi: 10.1038/s41598-022-07394-y. PMID: 35241721; PMCID: PMC8894377.

4: Mir BA, Albrecht E, Ali A, Hansson O, Maak S. MicroRNA-100 Reduced Fetal Bovine Muscle Satellite Cell Myogenesis and Augmented Intramuscular Lipid Deposition by Modulating IGF1R. Cells. 2022 Jan 28;11(3):451. doi: 10.3390/cells11030451. PMID: 35159261; PMCID: PMC8833961.

5: Li J, Zhu H, Yang Q, Xiao H, Wu H, Fang Z, Li W, Cai M. Identification of Molecular Subtypes and Potential Small-Molecule Drugs for Esophagus Cancer Treatment Based on m6A Regulators. J Oncol. 2022 Jan 13;2022:5490461. doi: 10.1155/2022/5490461. PMID: 35069736; PMCID: PMC8776445.

6: de Billy E, Pellegrino M, Orlando D, Pericoli G, Ferretti R, Businaro P, Ajmone-Cat MA, Rossi S, Petrilli LL, Maestro N, Diomedi-Camassei F, Pezzullo M, De Stefanis C, Bencivenga P, Palma A, Rota R, Del Bufalo F, Massimi L, Weber G, Jones C, Carai A, Caruso S, De Angelis B, Caruana I, Quintarelli C, Mastronuzzi A, Locatelli F, Vinci M. Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant. Neuro Oncol. 2022 Jul 1;24(7):1150-1163. doi: 10.1093/neuonc/noab300. PMID: 34964902; PMCID: PMC9248389.

7: Stalnecker CA, Grover KR, Edwards AC, Coleman MF, Yang R, DeLiberty JM, Papke B, Goodwin CM, Pierobon M, Petricoin EF, Gautam P, Wennerberg K, Cox AD, Der CJ, Hursting SD, Bryant KL. Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors. Cancer Res. 2022 Feb 15;82(4):586-598. doi: 10.1158/0008-5472.CAN-21-1443. PMID: 34921013; PMCID: PMC8886214.

8: Patel H, Mishra R, Yacoub N, Alanazi S, Kilroy MK, Garrett JT. IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma. Cancers (Basel). 2021 Nov 22;13(22):5863. doi: 10.3390/cancers13225863. PMID: 34831014; PMCID: PMC8616282.

9: Hassan MS, Cwidak N, Johnson C, Däster S, Eppenberger-Castori S, Awasthi N, Li J, Schwarz MA, von Holzen U. Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer. Front Pharmacol. 2021 Sep 21;12:746385. doi: 10.3389/fphar.2021.746385. PMID: 34621175; PMCID: PMC8490822.

10: Lehman CE, Spencer A, Hall S, Shaw JJP, Wulfkuhle J, Petricoin EF, Bekiranov S, Jameson MJ, Gioeli D. IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK. Sci Rep. 2021 May 24;11(1):10826. doi: 10.1038/s41598-021-90289-1. PMID: 34031486; PMCID: PMC8144381.

11: Mills JV, Osher E, Rieunier G, Mills IG, Macaulay VM. IGF-1R nuclear import and recruitment to chromatin involves both alpha and beta subunits. Discov Oncol. 2021;12(1):13. doi: 10.1007/s12672-021-00407-8. Epub 2021 Apr 29. PMID: 33969359; PMCID: PMC8084799.

12: Li Y, Lu K, Zhao B, Zeng X, Xu S, Ma X, Zhi Y. Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer. J Gastrointest Oncol. 2020 Dec;11(6):1135-1145. doi: 10.21037/jgo-20-210. PMID: 33456988; PMCID: PMC7807270.

13: Zeng B, Liao X, Liu L, Zhang C, Ruan H, Yang B. Thyroid hormone mediates cardioprotection against postinfarction remodeling and dysfunction through the IGF-1/PI3K/AKT signaling pathway. Life Sci. 2021 Feb 15;267:118977. doi: 10.1016/j.lfs.2020.118977. Epub 2020 Dec 28. PMID: 33383053.

14: 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.

15: Beauchamp RL, Erdin S, Witt L, Jordan JT, Plotkin SR, Gusella JF, Ramesh V. mTOR kinase inhibition disrupts neuregulin 1-ERBB3 autocrine signaling and sensitizes NF2-deficient meningioma cellular models to IGF1R inhibition. J Biol Chem. 2021 Jan-Jun;296:100157. doi: 10.1074/jbc.RA120.014960. Epub 2020 Dec 9. PMID: 33273014; PMCID: PMC7949095.

16: 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.

17: Wang Q, Zhang Y, Zhu J, Zheng H, Chen S, Chen L, Yang HS. IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas. Signal Transduct Target Ther. 2020 Aug 26;5(1):153. doi: 10.1038/s41392-020-0204-0. PMID: 32843616; PMCID: PMC7447751.

18: Sia KCS, Zhong L, Mayoh C, Norris MD, Haber M, Marshall GM, Raftery MJ, Lock RB. Targeting TSLP-Induced Tyrosine Kinase Signaling Pathways in CRLF2-Rearranged Ph-like ALL. Mol Cancer Res. 2020 Dec;18(12):1767-1776. doi: 10.1158/1541-7786.MCR-19-1098. Epub 2020 Aug 14. PMID: 32801162.

19: Bohin N, McGowan KP, Keeley TM, Carlson EA, Yan KS, Samuelson LC. Insulin- like Growth Factor-1 and mTORC1 Signaling Promote the Intestinal Regenerative Response After Irradiation Injury. Cell Mol Gastroenterol Hepatol. 2020;10(4):797-810. doi: 10.1016/j.jcmgh.2020.05.013. Epub 2020 Jun 2. PMID: 32502530; PMCID: PMC7502577.

20: Yang M, Jaaks P, Dry J, Garnett M, Menden MP, Saez-Rodriguez J. Stratification and prediction of drug synergy based on target functional similarity. NPJ Syst Biol Appl. 2020 Jun 2;6(1):16. doi: 10.1038/s41540-020-0136-x. PMID: 32487991; PMCID: PMC7265486.



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. )