BMS-777607

BMS-777607は一種のMet関連の阻害剤で、無細胞実験でc-Met、Axl、RonとTyro3に作用する時のIC50値が3.9 nM、1.1 nM、1.8 nMと4.3 nMにそれぞれ分かれることです。BMS-777607は、Met関連ターゲットに作用する選択性はLck、VEGFR-2とTrkA/Bに作用する選択性より40倍が高くなって、他の受容体と非受容体のキナーゼに作用する選択性より500倍が高くなります。臨床 1/2期。

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BMS-777607 化学構造
分子量: 512.89

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製品説明

  • Compare c-Met Inhibitors
    c-Met製品生物活性の比較
  • 研究分野
  • BMS-777607のメカニズム

製品の説明

生物活性

製品説明 BMS-777607は一種のMet関連の阻害剤で、無細胞実験でc-Met、Axl、RonとTyro3に作用する時のIC50値が3.9 nM、1.1 nM、1.8 nMと4.3 nMにそれぞれ分かれることです。BMS-777607は、Met関連ターゲットに作用する選択性はLck、VEGFR-2とTrkA/Bに作用する選択性より40倍が高くなって、他の受容体と非受容体のキナーゼに作用する選択性より500倍が高くなります。臨床 1/2期。
ターゲット c-Met Axl Ron Tyro3
IC50 3.9 nM 1.1 nM 1.8 nM 4.3 nM [1]
In vitro試験 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-16 MYjLbY5ie2ViYYPzZZk> Mm\XSG1UVw>? NXXB[JRkcW6qaXLpeJMhVWW2IHvpcoF{\SC5aYToJGlEPTBib3[gNVAxKG6P NGe1R3AyQTJ4MEexNS=>
H1993 NHPPSlFIem:5dHigbY5pcWKrdH;yfUBie3OjeR?= NInLTVR,OTBizszN NYi2ZlE5TE2VTx?= NELjSo1KSzVyPUG1NEBvVQ>? MWexPVI3ODdzMR?=
U87 MX;Hdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MV7+NVAh|ryP MVLEUXNQ MWrJR|UxRTF4MDDuUS=> NYrxe5RvOTl{NkC3NVE>
PC-3 MX;GeY5kfGmxbjDhd5NigQ>? NYXKU2xnOC5zIN88US=> MojKSG1UVw>? M4m0eYV5cGmkaYTzJIlvcGmkaYTvdpkh\W[oZXP0JI9vKEiJRj3pcoR2[2WmIHPlcIwhe2OjdITldolv\w>? NXewZZFMOjB3MUW5OFM>
DU145 MXzGeY5kfGmxbjDhd5NigQ>? M3:wOVAvOSEQvF2= Ml\GSG1UVw>? NVfWSnY5\XiqaXLpeJMhcW6qaXLpeI9zgSCnZn\lZ5Qhd25iSFfGMYlv\HWlZXSgZ4VtdCC|Y3H0eIVzcW6p MXiyNFUyPTl2Mx?=
PC-3 MkP1SpVv[3Srb36gZZN{[Xl? Mm\kNE4xOSEQvF2= NXvxbY5WTE2VTx?= M1TGUJN2eHC{ZYPz[ZMhUEeILXnu[JVk\WRiY3XscEBucWe{YYTpc44> MWCyNFUyPTl2Mx?=
DU145 NFnZWGRHfW6ldHnvckBie3OjeR?= NXTDc21wOC5yMTFOwG0> M1jmRWROW09? MULzeZBxemW|c3XzJGhITi2rbnT1Z4VlKGOnbHygcYloemG2aX;u M3TGfFIxPTF3OUSz
PC-3 M2K4[mZ2dmO2aX;uJIF{e2G7 NWT2cpE6OC5zIN88US=> MofpSG1UVw>? MnnLbY1x[Wm{czDIS2YudWWmaXH0[YQh[2WubDDpcpZie2mxbh?= MoLWNlA2OTV7NEO=
DU145 Ml35SpVv[3Srb36gZZN{[Xl? NHHyPXExNjFizszN MUXEUXNQ MUTpcZBicXK|IFjHSk1u\WSrYYTl[EBk\WyuIHnueoF{cW:w MV:yNFUyPTl2Mx?=
PC-3 MUnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? NXXCR4FlhjFyIN88US=> MmjKSG1UVw>? MmXRdoVlfWOnczDj[YxtKHC{b3zp[oVz[XSrb36= MlfDNlA2OTV7NEO=
KHT MUTLbY5ie2ViYYPzZZk> MWXEUXNQ MXnicI9kc3NidHjlJIMuVWW2IIPp[45idGmwZzDwZZRpf2G7IIfpeIghUUN3MDDv[kAyOCCwTR?= MVWyNlI5PjV{Mx?=
KHT M{jLWmZ2dmO2aX;uJIF{e2G7 M{DhR54yKM7:TR?= NWjoW3VuTE2VTx?= MorJdJJmfmWwdIOgd5BwdnSjbnXveZMhU0iWIHPlcIwhe2OjdITldolv\yC5aYToJGlEPTBib3[gNE4yNTBwNTFOwG0> MlLCNlIzQDZ3MkO=
KHT Ml3zSpVv[3Srb36gZZN{[Xl? M4DSVp4xNjVizszN MV3EUXNQ NF:4cGVqdmirYnn0d{Bk\WyuIH3p[5JifGmxbh?= MWeyNlI5PjV{Mx?=
KHT NFq5NFBHfW6ldHnvckBie3OjeR?= M4\DOJ4xNjVizszN M3qzcmROW09? MVPpcohq[mm2czDj[YxtKGmwdnHzbY9v NHe0bHEzOjJ6NkWyNy=>
KHT MWjHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MkHuglExKM7:TR?= NXvXUnoxTE2VTx?= NEPGXGNqdmirYnn0d{BMUFRiY3XscEBxem:uaX\ldoF1cW:w NF\2SnEzOjJ6NkWyNy=>
T-47D MVXHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MlHXglUh|ryP MXjEUXNQ M{DmVolvcGmkaYTzJINmdGxicILvcIln\XKjdHnvci=> MWKyN|Q3QDV{OR?=
ZR-75-1 MWnHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>? MX3+OUDPxE1? MUXEUXNQ NGr5V5ZqdmirYnn0d{Bk\WyuIIDyc4xq\mW{YYTpc44> NH7GbFQzOzR4OEWyPS=>
T-47D NFnKfm1HfW6ldHnvckBie3OjeR?= NEPBW4QyOCEQvF2= MkT2SG1UVw>? NY[zemhUUW6mdXPld{Bxd2y7cHzvbYR6KGK7IEi2JEU> M3LMZ|I{PDZ6NUK5
ZR-75-1 MWnGeY5kfGmxbjDhd5NigQ>? NX;aVW1rOTBizszN NF\SWmVFVVOR NFXtd4ZKdmS3Y3XzJJBwdHmybH;p[Jkh[nliOEil NHnwO|YzOzR4OEWyPS=>
T-47D NWfpOoplTnWwY4Tpc44h[XO|YYm= NXvt[3hKOTBizszN NVn5e25JTE2VTx?= NWfLRWt2cW6qaXLpeJMhSVWUSz3CJIZ2dmO2aX;uJIFv\CCrbnT1Z4V{KGm2czDwdo91\WmwIHTl[5Ji\GG2aX;u NUWzTG9xOjN2Nki1Nlk>
CHRF NGjKRVJHfW6ldHnvckBie3OjeR?= M1vEN|ExKM7:TR?= M1LVNWROW09? NF7GPW9qdmirYnn0d{Bk\WyuIHTpeol{cW:w NVq5c3NsOjV|MES5NFA>
HPDE NVTyN5dkTnWwY4Tpc44h[XO|YYm= MlLINVAh|ryP MWXEUXNQ MnryZoxw[2u|IHPvcpN1cXS3dHn2[UBi[3SrdnH0bY9vKGGwZDDk[YNz\WG|ZXSgRWtVKHOrZ37hcIlv\w>? NF:xPHIzPjR5N{OxOC=>
U118MG M4e2UmtqdmG|ZTDhd5NigQ>? M33GPJ4{KM7:TR?= NHPJXoNFVVOR NETGR|VjdG:la4OgRXhNKHCqb4PwbI9zgWyjdHnvci=> NXzv[4RHOjZ6NEi1NlQ>
SF126 MUnLbY5ie2ViYYPzZZk> M1f4Rp4{KM7:TR?= M2nzU2ROW09? NXLOfpVr[myxY3vzJGFZVCCyaH;zdIhwenmuYYTpc44> M{\kXlI3QDR6NUK0
U118MG NF64fFdEgXSxeHnjbZR6KGG|c3H5 MXexNk42KM7:TR?= M1q1UGROW09? MYnk[YNz\WG|ZYOg[4xqd22jIHPlcIwhfmmjYnnsbZR6 MWSyOlg1QDV{NB?=
SF126 NIHidYVEgXSxeHnjbZR6KGG|c3H5 M3j0O|EzNjVizszN M{nUW2ROW09? Mn65[IVkemWjc3XzJIdtcW:vYTDj[YxtKH[rYXLpcIl1gQ>? MkDsNlY5PDh3MkS=
U118MG MXfBdI9xfG:|aYOgZZN{[Xl? M3jkOlEzNjVizszN NETmOVFFVVOR NY\UPFZQcW6mdXPld{BodGmxbXGgZ4VtdCCjcH;weI9{cXN? MojFNlY5PDh3MkS=
SF126 M4nnTmFxd3C2b4Ppd{Bie3OjeR?= MWCxNk42KM7:TR?= NWnjWnV4TE2VTx?= NEPnNY9qdmS3Y3XzJIdtcW:vYTDj[YxtKGGyb4D0c5Nqew>? MnPaNlY5PDh3MkS=
U118MG MmH4SpVv[3Srb36gZZN{[Xl? MUOxNk42KM7:TR?= NIrVdVVFVVOR MXXicI9kc3NiZ3zpc41iKGOnbHygcYloemG2aX;uJIFv\CCrbo\hd4l3\SCpcn;3eIgheGG2dHXyci=> NUPn[lBFOjZ6NEi1NlQ>
SF126 NX;NXZhwTnWwY4Tpc44h[XO|YYm= MWCxNk42KM7:TR?= Mo\WSG1UVw>? MoLoZoxw[2u|IHfsbY9u[SClZXzsJI1q\3KjdHnvckBidmRiaX72ZZNqfmViZ4Lve5RpKHCjdITldo4> M4XyRVI3QDR6NUK0

... Click to View More Cell Line Experimental Data

In vivo試験 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]
臨床試験 Phase I/II has been completed in the study to find the maximum tolerated dose and the preliminary activity of BMS-777607 in subjects with advanced or metastatic solid tumors, hormone refractory prostate cancer, head and neck squamous cell carcinoma, and t
特集 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.

プロトコル (参考用のみ)

キナーゼアッセイ: [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.

細胞アッセイ: [3]

細胞株 Rodent fibrosarcoma KHT cells
濃度 Dissolved in DMSO as a stock solution (10 mM), final concentration ~10 μM.
反応時間 2, 24 and 96 hours
実験の流れ 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.

動物実験: [3]

動物モデル Rodent fibrosarcoma KHT cells are established in female C3H/HeJ mice.
製剤 Dissolved in DMSO as a stock solution (10 mM).
投薬量 10-25 mg/kg.
投与方法 Oral gavage once daily.

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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

参考

化学情報

Download BMS-777607 SDF
分子量 512.89
化学式

C25H19ClF2N4O4

CAS No. 1025720-94-8
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 47 mg/mL (91.63 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 4% DMSO+30% PEG 300+ddH2O 5mg/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.
化学名 N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

文献中の引用 (9)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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