LY2228820 化学構造
分子量: 612.74

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製品説明

  • Compare p38 MAPK Inhibitors
    p38 MAPK製品生物活性の比較
  • 研究分野

製品の説明

生物活性

製品説明 LY2228820は、p38 MAPKの新しくて強力な阻害剤で、 IC50 が7 nMになる。
ターゲット p38α
IC50 7 nM [1]
In vitro試験 LY2228820 inhibits p38α, as well as the level of phosphoMAPKAPK-2 (pMK2) in RAW 264.7 cells, with IC50 values of 7 nM and 34.3 nM, respectively. Furthermore, LY2228820 inhibits lipopolysaccharide (LPS)-induced TNFα formation in murine peritoneal macrophages, with IC50 of 5.2 nM. [1] In multiple myeloma (MM) cells, including INA6, RPMI-8226, U266, and RPMI-Dox40, LY2228820 (200 nM–800 nM) significantly blocks p38MAPK signaling, as revealed by its inhibition on phosphorylation of HSP27, a downstream target of p38MAPK, without affecting the expression level of HSP27. LY2228820 (200 nM–400 nM) enhances bortezomib-induced cytotoxicity and apoptosis, but LY2228820 alone doesn't inhibit the growth of MM.1S cells. LY2228820 (200 nM–800 nM) also inhibits secretion of IL-6 and MIP-1α in long-term BM stromal cells (LT-BMSCs), BM mononuclear cells (BMMNCs), peripheral blood (PB) CD138+, CD138 or PB CD14+ cells. LY2228820 (400 nM–800 nM) also blocks osteoclastogenesis from CD14+ cells. [2]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
RPMI-8226 NEXsW5RMcW6jc3WgZZN{[Xl? NHThPIR,QDByIH7N NU\uZphvTE2VTx?= MlvVbY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJGhUWDJ5 M{LWUlE5Ozl5M{S1
U266 MlfoT4lv[XOnIHHzd4F6 MXj+PFAxKG6P NYrCdoZWTE2VTx?= MV;pcohq[mm2czDwbI9{eGixconsZZRqd25ib3[gTHNROjd? M4P5clE5Ozl5M{S1
MM.1S M4H4c2tqdmG|ZTDhd5NigQ>? NGDZcmJ,QDByIH7N M1L3fGROW09? MnXUbY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJGhUWDJ5 Ml32NVg{QTd|NEW=
RPMI-Dox40 MXnLbY5ie2ViYYPzZZk> MnnIglgxOCCwTR?= MlfZSG1UVw>? M{HYWIlvcGmkaYTzJJBpd3OyaH;yfYxifGmxbjDv[kBJW1B{Nx?= MWWxPFM6PzN2NR?=
RPMI-LR5 MUXLbY5ie2ViYYPzZZk> NY\nVnpLhjhyMDDuUS=> MVzEUXNQ NUi1UW9QcW6qaXLpeJMheGixc4Doc5J6dGG2aX;uJI9nKEiVUEK3 NX3IbmlFOTh|OUezOFU>
INA-6 M{HKU2tqdmG|ZTDhd5NigQ>? M4\6XZ45ODBibl2= NW[yWYFPTE2VTx?= MoXGbY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJGhUWDJ5 NWmxRYc1OTh|OUezOFU>
RPMI-8226 MmPZR5l1d3irY3n0fUBie3OjeR?= NEXpcFV,OTByMDDuUS=> NFrCdolFVVOR M32wN45wKHOrZ37p[olk[W62IHP5eI91d3irY3n0fS=> MmP6NVg{QTd|NEW=
U266 NH\aPWpEgXSxeHnjbZR6KGG|c3H5 M331c54yODByIH7N M4HYcWROW09? MnTjco8he2mpbnnmbYNidnRiY4n0c5RwgGmlaYT5 M2XSXlE5Ozl5M{S1
MM.1S Mn;nR5l1d3irY3n0fUBie3OjeR?= MYX+NVAxOCCwTR?= MW\EUXNQ MWTuc{B{cWewaX\pZ4FvfCCleYTveI95cWOrdIm= NXrQS2M1OTh|OUezOFU>
RPMI-Dox40 Mnz1R5l1d3irY3n0fUBie3OjeR?= MXP+NVAxOCCwTR?= MUfEUXNQ MmPoco8he2mpbnnmbYNidnRiY4n0c5RwgGmlaYT5 MmnkNVg{QTd|NEW=
RPMI-LR5 MYXDfZRwgGmlaYT5JIF{e2G7 M4PyT54yODByIH7N NIP0NG5FVVOR NYTUc5JLdm9ic3nncolncWOjboSgZ5l1d3SxeHnjbZR6 M3rRVFE5Ozl5M{S1
INA-6 NFLDRXZEgXSxeHnjbZR6KGG|c3H5 NH;OU2h,OTByMDDuUS=> NGDMWIdFVVOR MlPwco8he2mpbnnmbYNidnRiY4n0c5RwgGmlaYT5 MlrCNVg{QTd|NEW=
CD14+ NXXKToZxTnWwY4Tpc44h[XO|YYm= MlWzglgxOCCwTR?= NFWwfFlFVVOR NGq3PYdqdmirYnn0d{Bwe3Snb3PsZZN1d2enbnXzbZMh\nKxbTDDSFE1KHCxc3n0bZZmKGOnbHzz NGLzfJgyQDN7N{O0OS=>
U-87-MG MWfGeY5kfGmxbjDhd5NigQ>? NVLscXRxOSEQvF2= M2e1fGROW09? NXXwNWV2emWmdXPld{B1fW2xcj3kdol3\W5iY3;y[EBnd3KvYYTpc44> NHmzUlkzOzN|NUWwOi=>
MDA-MB-231 Mo[5SpVv[3Srb36gZZN{[Xl? M2rFOlEh|ryP MlSxSG1UVw>? MnTqdoVlfWOnczD0eY1wei2mcnn2[Y4h[2:{ZDDmc5Ju[XSrb36= M3vQTlI{OzN3NUC2
A-2780 Mmm5SpVv[3Srb36gZZN{[Xl? NX\0WFE5OSEQvF2= NIThUpVFVVOR NYfXZWRxemWmdXPld{B1fW2xcj3kdol3\W5iY3;y[EBnd3KvYYTpc44> MVSyN|M{PTVyNh?=
SK-OV-3 NWnUVJFITnWwY4Tpc44h[XO|YYm= NGOzRY4yKM7:TR?= NVXKcIxtTE2VTx?= NGrFd|lz\WS3Y3XzJJR2dW:{LXTybZZmdiClb4LkJIZwem2jdHnvci=> NGDkdGozOzN|NUWwOi=>
LXFA-629 M1jEPGZ2dmO2aX;uJIF{e2G7 NULRb2VJOSEQvF2= MlLCSG1UVw>? MnS3doVlfWOnczD0eY1wei2mcnn2[Y4h[2:{ZDDmc5Ju[XSrb36= MUmyN|M{PTVyNh?=
NCI-H1650 NFi2NIFHfW6ldHnvckBie3OjeR?= MmLkNUDPxE1? MWfEUXNQ NX:w[49MemWmdXPld{B1fW2xcj3kdol3\W5iY3;y[EBnd3KvYYTpc44> NEOzb3UzOzN|NUWwOi=>
PC-3 NUHud3d4TnWwY4Tpc44h[XO|YYm= NXTofI57OSEQvF2= M{jNV2ROW09? NEni[4Jz\WS3Y3XzJJR2dW:{LXTybZZmdiClb4LkJIZwem2jdHnvci=> NVK4ZY1nOjN|M{W1NFY>
RAW264.7 NEnURWNHfW6ldHnvckBie3OjeR?= NF3EVXZ,OjBizszN NXPINnRSTE2VTx?= NXXPd|Q3cW6qaXLpeJMhSW6rc3;tfYNqdi2|dHnteYxifGWmIF3LNkBxcG:|cHjvdplt[XSrb36ge4l1cCCLQ{WwJI9nKDN3LkOgcm0> NGnJPW0zPDN3NkixOC=>
mouse peritoneal macrophages MkTQSpVv[3Srb36gZZN{[Xl? MVX+NlAh|ryP MWTEUXNQ M1\vRmxRWy:LRl6t{tPjiJO|dHnteYxifGWmIGTOSk3PuSCycn;keYN1cW:wIIfpeIghUUN3MDDv[kA3NjNibl2= NWXEe5BzOjR|NU[4NVQ>
A549 M3rme2Z2dmO2aX;uJIF{e2G7 NVfMeYZ6hjJyIN88US=> M3PCN2ROW09? MmLybY5pcWKrdIOgUHBUNWmwZIXj[YQhS1iFTEigdJJw\HWldHnvckB4cXSqIFnDOVAhd2ZiMUS0Mlkhdk1? M2m4SlI1OzV4OEG0
MDA-231 MnjySpVv[3Srb36gZZN{[Xl? M{P3NZ4yOCEQvF2= M3[4epN2eHC{ZYPz[ZMhTEuNLUGg[ZhxemW|c3nvci=> NUS1XZplOjZ2MEe4OFM>
MCF-7 MVvGeY5kfGmxbjDhd5NigQ>? M3jpWZ4yOCEQvF2= MUHzeZBxemW|c3XzJGRMUy1zIHX4dJJme3Orb36= MXqyOlQxPzh2Mx?=
MDA-435 NWDTRoRQTnWwY4Tpc44h[XO|YYm= MlOyglExKM7:TR?= MYjzeZBxemW|c3XzJGRMUy1zIHX4dJJme3Orb36= MnOzNlY1ODd6NEO=
PC3 NUHqOpljTnWwY4Tpc44h[XO|YYm= MmHFglExKM7:TR?= NGLVV3hFVVOR NVvRdWNje3WycILld5NmeyCGS1utNUBmgHC{ZYPzbY9v NUfmSVd1OjZ7MUO2NFg>

... Click to View More Cell Line Experimental Data

In vivo試験 In LPS-induced mice, LY2228820 effectively inhibits the formation of TNFα with a threshold minimum 50% effective dose (TMED50) less than 1 mg/kg. In a rat model of collagen-inducedarthritis (CIA), LY2228820 displays potent effects on paw swelling, bone erosion, and cartilage destruction, with a threshold minimum 50% effective dose (TMED50)of 1.5 mg/kg. [1]
臨床試験 LY2228820 is currently under a Phase I clinical trial for the treatment of advanced cancer.
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Inhibition of p38α Inhibition of p38α is determined using recombinant human p38α in a standard filter binding protocol using ATP[γ-33P] and EGFR 21-mer peptide as substrate. Functional inhibition of TNFα in murine peritoneal macrophages is determined using LPS stimulation in the presence of LY2228820. To assess p38α activity in cells more directly, RAW 264.7 cells are treated with LY2228820 and then stimulated with anisomycin. The level of p38α activity is detected using a phosphoMAPKAPK-2 (pMK2) (Thr 334) antibody which reacts with a residue specifically phosphorylated by p38α.

細胞アッセイ: [2, 3]

細胞株 MM cells, including INA6, RPMI-8226, U266, and RPMI-Dox40
濃度 200 nM–800 nM
反応時間 48 hours
実験の流れ MTT assays and APO 2.7 staining are performed to assess cellular proliferation and induction of apoptosis, respectively. Viability is expressed as percent viable cells. Apoptosis in cells is evaluated by APO 2.7 staining. For detection of mitochondrial membrane protein 7A6 expressed in apoptotic cells, cells are incubated with APO 2.7 reagent for 20 min. Expression of APO 2.7 is determined using an EPICS XL flow cytometer.

動物実験: [1]

動物モデル Lipopolysaccharide (LPS)-induced Balb/c mice
製剤 Dissolved in 1% CMC/0.25% Tween 80 in water
投薬量 0–20 mg/kg
投与方法 Oral bid dosing for 14 days

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 LY2228820 SDF
分子量 612.74
化学式

C24H29FN6.2CH4O3S

CAS No. 862507-23-1
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 4 mg/mL warmed (6.52 mM)
100 mg/mL warmed (163.2 mM)
エタノール 3 mg/mL (4.89 mM)
In vivo Saline 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.
化学名 5-(2-tert-butyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-amine dimethanesulfonate

カスタマーフィードバック (4)


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Rating
Source Blood, 2012, 119, 6255-8. LY2228820 purchased from Selleck
Method Screening procedure
Cell Lines CB CD34<sup>+</sup> cells
Concentrations 100 nM
Incubation Time 14 days
Results To first focus on MAPK14 as it is readily druggable by several pharmacologic inhibitors and has distinct expression in CD34<sup>+</sup> cells.Validation experiments showed that p38α inhibition by a small molecule inhibitor enhanced the frequency of CD34<sup>+</sup> cells during culture, introducing MAPK14/p38α as a promising target to manipulate ex vivo HSPC activity.

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Rating
Source Mol Cancer Ther, 2011, 10, 2244-56. LY2228820 purchased from Selleck
Method Cell Cycle Distribution Assays
Cell Lines U87EV cell, U87PTEN cell
Concentrations
Incubation Time
Results Treatment of either U87 EV or U87 PTEN cells with LY2228820 alone had little effect on cell cycle distribution as compared to control, however cotreatment with both rapamycin and LY2228820 resulted in a substantial increase in the percentage of cells arrested in G1 in quiescent AKT-containing U98 PTEN cells (32% G1/G0 LY2228820 alone to 54% G1/G0 cotreatment). LY2228820 alone had no significant affects on the cell cycle distributions of LN229 AKT-MER nor LN229 EV cells (Fig D)

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Rating
Source Acta Pharmacol Sin, 2014, 35, 339-50. LY2228820 purchased from Selleck
Method Western blot
Cell Lines Human umbilical vein endothelial cells
Concentrations 10 uM
Incubation Time 1 h
Results The inhibitory effects on PI3K and Akt were verified using the p38 inhibitor, LY2228820. As shown in Figure, the short-term incubation of HUVECs with LY2228820 did not affect p38 MAPK, although it did reduce PI3K and Akt activation.

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Rating
Source Dr. Yong-Weon Yi from Georgetown University Medical Center. LY2228820 purchased from Selleck
Method MTT assays
Cell Lines SUM149PT cells
Concentrations 0.12-10 μM
Incubation Time 72 h
Results

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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