BMS-777607

Catalog No.S1561

BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM in cell-free assays, 40-fold more selective for Met-related targets versus Lck, VEGFR-2, and TrkA/B, and more than 500-fold greater selectivity versus all other receptor and non receptor kinases. Phase 1/2.

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BMS-777607 Chemical Structure

BMS-777607 Chemical Structure
Molecular Weight: 512.89

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Product Information

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  • Research Area
  • Inhibition Profile
  • BMS-777607 Mechanism

Product Description

Biological Activity

Description BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM in cell-free assays, 40-fold more selective for Met-related targets versus Lck, VEGFR-2, and TrkA/B, and more than 500-fold greater selectivity versus all other receptor and non receptor kinases. Phase 1/2.
Targets Axl [1]
(Cell-free assay)
RON [1]
(Cell-free assay)
Met [1]
(Cell-free assay)
Tyro3 [1]
(Cell-free assay)

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IC50 1.1 nM 1.8 nM 3.9 nM 4.3 nM
In vitro BMS-777607 is a selective ATP-competitive Met kinase inhibitor which potently blocks the autophosphorylation of c-Met with IC50 of 20 nM in GTL-16 cell lysates, and demonstrates selective inhibition of proliferation in Met-driven tumor cell lines, such as GTL-16 cell line, H1993 and U87. [1] BMS-777607 inhibits hepatocyte growth factor (HGF)-triggered c-Met autophosphorylation with IC50 of <1 nM in PC-3 and DU145 prostate cancer cells. BMS 777607 has little effect on tumor cell growth, but exhibits inhibitory effect on HGF-induced cell scattering in PC-3 and DU145 cells, with almost complete inhibition at 0.5 μM. BMS 777607 also suppresses stimulated cell migration and invasion in a dose-dependent fashion (IC50 < 0.1 μM) in both cell lines. [2] Application of BMS 777607 (~10 μM) to the highly metastatic murine KHT cells for 2 hours potently eliminates basal levels of autophosphorylated c-Met with IC50 of 10 nM without affecting the total c-Met, leading to dose-dependent inhibition of phosphorylation of downstream signaling molecules including ERK, Akt, p70S6K and S6. Treatment with BMS-777607 (~1 μM) for 24 hours potently inhibits the KHT cell scatter, motility and invasion at doses in the nanomolar range which consists with MET gene knockdown, and modestly affects cell proliferation and colony formation. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
GTL-16NET4OllMcW6jc3WgZZN{[Xl?MUjEUXNQNEjYfmVqdmirYnn0d{BO\XRia3nuZZNmKHerdHigTWM2OCCxZjCxNFAhdk1?NE\rXI0yQTJ4MEexNS=>
H1993NVjEbGZIT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm=NVnKTlF7hjFyIN88US=>NUD6W4N4TE2VTx?=MkTKTWM2OD1zNUCgcm0>M4S2XFE6OjZyN{Gx
U87M4jBc2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7MXr+NVAh|ryPM3LtUmROW09?NY\nNo9mUUN3ME2xOlAhdk1?M37GblE6OjZyN{Gx
PC-3MY\GeY5kfGmxbjDhd5NigQ>?NYfFUVI6OC5zIN88US=>MnTGSG1UVw>?M3jhRYV5cGmkaYTzJIlvcGmkaYTvdpkh\W[oZXP0JI9vKEiJRj3pcoR2[2WmIHPlcIwhe2OjdITldolv\w>?MYqyNFUyPTl2Mx?=
DU145NEPreIxHfW6ldHnvckBie3OjeR?=NV7Dd|JWOC5zIN88US=>NUPjUWo5TE2VTx?=MXXlfIhq[mm2czDpcohq[mm2b4L5JIVn\mWldDDvckBJT0ZvaX7keYNm\CClZXzsJJNk[XS2ZYLpcoc>M1HtNFIxPTF3OUSz
PC-3NUTQfJozTnWwY4Tpc44h[XO|YYm=MkXkNE4xOSEQvF2=NYWxU4w5TE2VTx?=NWT6[|lQe3WycILld5NmeyCKR1[tbY5lfWOnZDDj[YxtKG2rZ4LheIlwdg>?NVzCcIRrOjB3MUW5OFM>
DU145MmXpSpVv[3Srb36gZZN{[Xl?NWjCPZp5OC5yMTFOwG0>NFrUZmxFVVORNHPGUWd{fXCycnXzd4V{KEiJRj3pcoR2[2WmIHPlcIwhdWmpcnH0bY9vM{XSS|IxPTF3OUSz
PC-3M2PtcGZ2dmO2aX;uJIF{e2G7NG[4fpMxNjFizszNNWHTOG11TE2VTx?=NUfGSHpjcW2yYXnyd{BJT0ZvbXXkbYF1\WRiY3XscEBqdn[jc3nvci=>NVnJdXdTOjB3MUW5OFM>
DU145NEjBU3BHfW6ldHnvckBie3OjeR?=NGC3TpQxNjFizszNMoniSG1UVw>?NGS3fWlqdXCjaYLzJGhITi2vZXTpZZRm\CClZXzsJIlvfmG|aX;uMoDFNlA2OTV7NEO=
PC-3NVe3NWpRT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm=NV;4OVl2hjFyIN88US=>NGrWNlJFVVORNF6ySYlz\WS3Y3XzJINmdGxicILvcIln\XKjdHnvci=>NFTSeVEzODVzNUm0Ny=>
KHTM1roe2tqdmG|ZTDhd5NigQ>?M4PIPGROW09?M1u1XIJtd2OtczD0bIUh[y2PZYSgd4lodmGuaX7nJJBifGi5YYmge4l1cCCLQ{WwJI9nKDFyIH7NMl;lNlIzQDZ3MkO=
KHTNHHQeWxHfW6ldHnvckBie3OjeR?=MoPYglEh|ryPMom4SG1UVw>?NG\2VYdxemW4ZX70d{B{eG:wdHHu[Y92eyCNSGSgZ4VtdCC|Y3H0eIVzcW6pIIfpeIghUUN3MDDv[kAxNjFvMD61JO69VQ>?M3X0SFIzOjh4NUKz
KHTMlPpSpVv[3Srb36gZZN{[Xl?MWT+NE42KM7:TR?=MYXEUXNQM3rwZYlvcGmkaYTzJINmdGxibXnndoF1cW:wNEDnXogzOjJ6NkWyNy=>
KHTNUPO[Y1wTnWwY4Tpc44h[XO|YYm=M4ftUZ4xNjVizszNNY\CcJlyTE2VTx?=NXHGVYFscW6qaXLpeJMh[2WubDDpcpZie2mxbh?=M4H3[lIzOjh4NUKz
KHTMX;Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?MXL+NVAh|ryPMo\pSG1UVw>?MkPkbY5pcWKrdIOgT2hVKGOnbHygdJJwdGmoZYLheIlwdg>?M1fadFIzOjh4NUKz
T-47DNGPJSHBIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=NEH5TGd,PSEQvF2=NGrkbZFFVVORNWrzV5IxcW6qaXLpeJMh[2WubDDwdo9tcW[ncnH0bY9vMmK4NlM1Pjh3Mkm=
ZR-75-1NYTFOW1WT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm=M{fCbZ42KM7:TR?=NWe0Z3B[TE2VTx?=NYjkNZM4cW6qaXLpeJMh[2WubDDwdo9tcW[ncnH0bY9vM1nVUlI{PDZ6NUK5
T-47DNH25V|NHfW6ldHnvckBie3OjeR?=NVjzbmdKOTBizszNMnzXSG1UVw>?M3HPeGlv\HWlZYOgdI9tgXCub3nkfUBjgSB6NjClNUDyeFdYOjN2Nki1Nlk>
ZR-75-1M{PZU2Z2dmO2aX;uJIF{e2G7MlruNVAh|ryPNXHzfnVQTE2VTx?=NUXsUo5iUW6mdXPld{Bxd2y7cHzvbYR6KGK7IEi4KS=>M3m5blI{PDZ6NUK5
T-47DNYPWT5RTTnWwY4Tpc44h[XO|YYm=MYWxNEDPxE1?MUfEUXNQM3Hjb4lvcGmkaYTzJGFWWktvQjDmeY5kfGmxbjDhcoQhcW6mdXPld{BqfHNicILveIVqdiCmZXfyZYRifGmxbh?=MkjzNlM1Pjh3Mkm=
CHRFMoPySpVv[3Srb36gZZN{[Xl?M{jRRlExKM7:TR?=M4jyNWROW09?NGW4SmtqdmirYnn0d{Bk\WyuIHTpeol{cW:wMUKyOVMxPDlyMB?=
HPDEMnLnSpVv[3Srb36gZZN{[Xl?M1TiSlExKM7:TR?=MY\EUXNQNFPRSnJjdG:la4OgZ49ve3SrdIX0bZZmKGGldHn2ZZRqd25iYX7kJIRm[3KnYYPl[EBCU1Ric3nncoFtcW6pNH\LVlAzPjR5N{OxOC=>
U118MGMmPVT4lv[XOnIHHzd4F6Mn;DglMh|ryPMV7EUXNQNYD4e5VQ[myxY3vzJGFZVCCyaH;zdIhwenmuYYTpc44>NGW1VlgzPjh2OEWyOC=>
SF126MkH5T4lv[XOnIHHzd4F6M3K4[Z4{KM7:TR?=M{L5VGROW09?MVPicI9kc3NiQWjMJJBpd3OyaH;yfYxifGmxbh?=M2XGdVI3QDR6NUK0
U118MGNHjhbplEgXSxeHnjbZR6KGG|c3H5MVOxNk42KM7:TR?=Ml[3SG1UVw>?M33MSIRm[3KnYYPld{BodGmxbXGgZ4VtdCC4aXHibYxqfHl?M1rDOFI3QDR6NUK0
SF126M{PwZmN6fG:6aXPpeJkh[XO|YYm=NFHLSowyOi53IN88US=>NX3RcG1NTE2VTx?=MXHk[YNz\WG|ZYOg[4xqd22jIHPlcIwhfmmjYnnsbZR6NXvacHlyOjZ6NEi1NlQ>
U118MGM1TyTWFxd3C2b4Ppd{Bie3OjeR?=NFzGT2EyOi53IN88US=>MmH3SG1UVw>?MWnpcoR2[2W|IHfsbY9u[SClZXzsJIFxd3C2b4Ppdy=>NIToe2IzPjh2OEWyOC=>
SF126MULBdI9xfG:|aYOgZZN{[Xl?MYKxNk42KM7:TR?=NV3ubWhPTE2VTx?=MYXpcoR2[2W|IHfsbY9u[SClZXzsJIFxd3C2b4Ppdy=>NV3PblB2OjZ6NEi1NlQ>
U118MGNGLJW4ZHfW6ldHnvckBie3OjeR?=M1jtTFEzNjVizszNNX\LPIc4TE2VTx?=NVvP[|hm[myxY3vzJIdtcW:vYTDj[YxtKG2rZ4LheIlwdiCjbnSgbY53[XOrdnWg[5Jwf3SqIIDheJRmem5?MWGyOlg1QDV{NB?=
SF126NEDCOW9HfW6ldHnvckBie3OjeR?=NW\iPJI5OTJwNTFOwG0>NXLZVlZCTE2VTx?=MmfnZoxw[2u|IHfsbY9u[SClZXzsJI1q\3KjdHnvckBidmRiaX72ZZNqfmViZ4Lve5RpKHCjdITldo4>NYDDT|RjOjZ6NEi1NlQ>

... Click to View More Cell Line Experimental Data

In vivo Oral administration of BMS 777607 (6.25-50 mg/kg) significantly reduces tumor volumes of the GTL-16 human tumor xenografts in athymic mice with no observed toxicity. [1] Administration of BMS 777607 (25 mg/kg/day) decreases the number of KHT lung tumor nodules (28.3%), improves the morphological hemorrhage, and significantly impairs the metastatic phenotype in the 6-8 week-old female C3H/HeJ mice injected with rodent fibrosarcoma KHT cells without apparent systemic toxicity compared to the control treatment. A low dose of BMS 777607 (10 mg/kg) also offers a mild but not significant inhibition of lung nodule formation compared to the vehicle control. [3]
Features A potent inhibitor of the Met family, and >40-fold selectivity vs. Lck, VEGFR2, and TrkA/B and >500-fold selective vs. other receptor and non-receptor kinases.

Protocol(Only for Reference)

Kinase Assay: [4]

Met Kinase Assay The kinase reaction consists of baculovirus expressed GST-Met, 3 μg of poly(Glu/Tyr), 0.12 μCi 33P γ-ATP, 1 μM ATP in 30 μL of kinase buffer (20 mM Tris-Cl, 5 mM MnCl2, 0.1 mg/mL BSA, 0.5 mM DTT). Reactions are incubated for 1 hour at 30 °C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 8%. TCA precipitates are collected onto GF/C unifilter plates using a Filtermate universal harvester, and the filters are quantitated using a TopCount 96-well liquid scintillation counter. Dose response curves are generated to determine the concentration required to inhibit 50% of substrate phosphorylation (IC50). BMS 777607 is dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at 10 concentrations, in duplicate.

Cell Assay: [3]

Cell lines Rodent fibrosarcoma KHT cells
Concentrations Dissolved in DMSO as a stock solution (10 mM), final concentration ~10 μM.
Incubation Time 2, 24 and 96 hours
Method KHT cells are exposed to serial dilution of BMS 777607 for 96 hours, then the MTT assay and trypan blue exclusion are used for the determination of cell proliferation and cell death, respectively. KHT cell colonies are incubated with BMS 777607 for 24 hours and then stained with crystal violet (0.1%) and photographed for the assessment of cell scattering. 2 mm scratch on the confluent KHT cell monolayer is made using a sterilized 1 ml pipette tip followed by treated with BMS-777607 for 24 hours, then the number of cells that have migrated into the denuded area is counted on 4 random fields for the evaluation of cell migration. For the examination of cell invasion, the commercial transwell inserts (8 μm pore membrane) pre-loaded with Matrigel are incubated with serum-free medium in the presence or absence of BMS 777607 at 37 °C for 2 hours to allow rehydration of Matrigel. Then cells suspended in serum-free medium are loaded onto the top chamber (5 × 103/insert) and complete medium (containing 10% FBS) is used in the lower chamber as a chemoattractant. After incubation for 24 hours, the Matrigel is removed and the inserts are stained with crystal violet. Invaded cells on the underside of the filter are photographed and counted.

Animal Study: [3]

Animal Models Rodent fibrosarcoma KHT cells are established in female C3H/HeJ mice.
Formulation Dissolved in DMSO as a stock solution (10 mM).
Dosages 10-25 mg/kg.
Administration Oral gavage once daily.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Schroeder GM, et al. J Med Chem, 2009, 52(5), 1251-1254.

[2] Dai Y, et al. Mol Cancer Ther, 2010, 9(6), 1554-1561.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01721148 Active, not recruiting Malignant Solid Tumour Aslan Pharmaceuticals October 2012 Phase 1
NCT00605618 Completed Advanced Solid Tumors Bristol-Myers Squibb March 2008 Phase 1|Phase 2

Chemical Information

Download BMS-777607 SDF
Molecular Weight (MW) 512.89
Formula

C25H19ClF2N4O4

CAS No. 1025720-94-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 47 mg/mL (91.63 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO+30% polyethylene glycol+1% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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