BMS-754807

• CAT Number: I000071
• CAS Number: 1001350-96-4
• Molecular Formula: C₂₃H₂₄FN₉O
• Molecular Weight: 461.49
• Purity: ≥95%
• Target: IGF1R
• Solubility: in DMSO > 10 mM
• Storage: 3 years -20C powder
• IC50: 1.8 nM/1.7 nM(IGF-1R/InsR) [1]
• InChI: 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
• InChIKey: LQVXSNNAFNGRAH-QHCPKHFHSA-N
• SMILES: CC1(CCCN1C2=NN3C=CC=C3C(=N2)NC4=NNC(=C4)C5CC5)C(=O)NC6=CN=C(C=C6)F

BMS-754807 is a potent and reversible inhibitor of IGF-1R/InsR with IC50 of 1.8 nM/1.7 nM, less potent to Met, Aurora A/B, TrkA/B and Ron, and shows little activity to Flt3, Lck, MK2, PKA, PKC etc.IC50 value: 1.8 nM/1.7 nM(IGF-1R/InsR) [1]Target: Multikinasein vitro: BMS-754807 effectively inhibits the growth of a broad range of human tumor cell lines of different histologic origins including mesenchymal (Ewing/’s, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, and gastric), and hematopoietic (multiple myeloma and leukemia), the IC50 values range from 5 nM to 365 nM for the most sensitive cell lines. BMS-754807 inhibits proliferation of IGF-1R-Sal cells and RH41 cells with IC50 of 7 nM and 5 nM. BMS-754807 inhibits phosphorylation of IGF-1R in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 13 nM, 6 nM and 21 nM. BMS-754807 inhibits phosphorylation of Akt in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 22 nM, 13 nM and 16 nM. BMS-754807 induces greater apoptosis in Rh41 cells by 24 hours as indicated by an increased sub-G1 peak (23.1%), compared with control (2.4%) [1]. BMS-754807 inhibits the phosphorylation of IGF-1R (IC50 = 13nM) and the downstream targets Akt (IC50 = 22nM) and MAPK (IC50 = 13nM) in the IGF-Sal cell line with IC50 consistent with the antiproliferative IC50 (7 nM) in this cell line. The crystal structure of BMS-754807 cocrystallized with the kinase domain of IGF-1R shows that the donor/acceptor/donor hydrogen bond triad with Met1052 and Glu1050 within the hinge region of the kinase [2]. BMS-754807 shows a median EC50 value of 0.62 μM against 23 cell lines in the pediatric preclinical testing program (PPTP) [3].in vivo: BMS-754807 (12.5mg/kg, orally) inhibits IGF-1R phosphorylation in tumor and serum in IGF-1R-Sal tumor–bearing nude mice. BMS-754807 inhibits tumor growth in a selected group of epithelial (IGF-1R-Sal, GEO, and Colo205), hematopoietic (JJN3), and mesenchymal (RD1 and Rh41) xenograft tumor models with TGI ranging from 53% to 115% [1]. BMS-754807 (6.25 mg/kg) achieves complete tumor growth inhibition in the transgenic-derived IGF-Sal tumor mouse model with correlated inhibition of pIGF-1R and pAKT. The protein binding for BMS-754807 ranges from of 98.5% in mouse plasma to 95.9% in human plasma. BMS-754807 results in clearance of 113 (mL/min)/kg, 20 (mL/min)/kg, 3.5 (mL/min)/kg and 41 (mL/min)/kg [2].

Reference

1:In vivo evaluation of IGF1R/IR PET ligand [18F]BMS-754807 in rodents. Prabhakaran J, Dewey SL, McClure R, Simpson NR, Tantawy MN, Mann JJ, Pham W, Kumar JS.Bioorg Med Chem Lett. 2017 Feb 15;27(4):941-943. doi: 10.1016/j.bmcl.2016.12.086. Epub 2017 Jan 7. PMID: 28094184 2: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 SE, Jones RA, Briah R, Murray P, Moorehead RA.BMC Res Notes. 2016 Mar 1;9:134. doi: 10.1186/s13104-016-1919-4. PMID: 26928578 Free PMC Article3: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 KG, Barton KL, Schroeder K, Misuraca KL, Hoeman C, Chung A, Crabtree DM, Cordero FJ, Singh R, Spasojevic I, Berlow N, Pal R, Becher OJ.PLoS One. 2015 Mar 6;10(3):e0118926. doi: 10.1371/journal.pone.0118926. eCollection 2015. PMID: 25748921 Free PMC Article4: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 F, Chang H, Greer A, Hillerman S, Reeves KA, Hurlburt W, Cogswell J, Patel D, Qi Z, Fairchild C, Ryseck RP, Wong TW, Finckenstein FG, Jackson J, Carboni JM.Mol Cancer Ther. 2015 Feb;14(2):620-30. doi: 10.1158/1535-7163.MCT-14-0794-T. Epub 2014 Dec 19. PMID: 25527633 Free Article5:Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R. Majo VJ, 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. PMID: 23743281 Free PMC Article6:BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor, enhances gemcitabine response in pancreatic cancer. Awasthi N, Zhang C, Ruan W, Schwarz MA, Schwarz RE.Mol Cancer Ther. 2012 Dec;11(12):2644-53. doi: 10.1158/1535-7163.MCT-12-0447. Epub 2012 Oct 9. PMID: 23047891 Free Article7: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. Lee SJ, Kim EJ, Lee HJ, Kim SY, Oh SJ, Ryu JS, Moon DH, Ahn JH, Kim SW.Invest New Drugs. 2013 Jun;31(3):506-15. doi: 10.1007/s10637-012-9874-y. Epub 2012 Sep 18. PMID: 22987020 8:Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer. Hou X, Huang F, Macedo LF, Harrington SC, Reeves KA, Greer A, Finckenstein FG, Brodie A, Gottardis MM, Carboni JM, Haluska P.Cancer Res. 2011 Dec 15;71(24):7597-607. doi: 10.1158/0008-5472.CAN-11-1080. Epub 2011 Oct 31. PMID: 22042792 Free PMC Article9:Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program. Kolb EA, Gorlick R, Lock R, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups C, Smith MA, Houghton PJ.Pediatr Blood Cancer. 2011 Apr;56(4):595-603. doi: 10.1002/pbc.22741. Epub 2010 Dec 22. PMID: 21298745 Free PMC Article10: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. Huang F, Hurlburt W, Greer A, Reeves KA, Hillerman S, Chang H, Fargnoli J, Graf Finckenstein F, Gottardis MM, Carboni JM.Cancer Res. 2010 Sep 15;70(18):7221-31. doi: 10.1158/0008-5472.CAN-10-0391. Epub 2010 Aug 31. PMID: 20807811 Free Article