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S63845
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
S63845图片
CAS NO:1799633-27-4
规格:≥98%
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW)829.26
FormulaC39H37ClF4N6O6S
CAS No.1799633-27-4 freebase
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: ≥ 100 mg/mL
Water: <1mg/mL
Ethanol: <1mg/mL
Solubility (In vivo)O=C(O)[C@@H](CC1=C(OCC2=CC=NN2CC(F)(F)F)C=CC=C1)OC3=C4C(SC(C5=CC=C(F)O5)=[C@@]4 [C@@]6=C(C)C(Cl)=C(OCCN7CCN(C)CC7)C=C6)=NC=N3.
Synonyms

S-63845; S 63845; S63845;

Exact Mass: 828.212

Chemical Name: (R)-2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid

实验参考方法
In Vitro

In vitro activity: S63845 is a potent, selective and high affinity small molecule inhibitor of MCL1 (myeloid cell leukemia 1) with Ki value < 1.2 nM. S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours. It is the first high affinity MCL-1 inhibitor with potent in vivo activity, it acts by binding to the BH3-binding groove of MCL-1 with a KD value of 0.19 nM for human MCL-1. S63845 is also highly selective against other BCL family proteins such as BCL-2 (Ki>10,000nM) and BCL-XL (Ki>10,000nM). S63845 showed the clear-on-target activity killing MCL-1-dependent cancer cells, including multiple myeloma, leukemia and lymphoma cells. It exhibited potent in vivo antitumor activity with an acceptable safety profile as monotherapy in the treatment of several cancer types.


Kinase Assay: 10 mM HEPES pH 7.4, 175 mM NaCl, 25 μM EDTA, 1 mM TCEP, 0.01% P20 and 1% DMSO is used as a running buffer. The ligand surface is generated using double His-tagged proteins. Serial dilutions of the compound in buffer are injected over the protein surface. All sample measurements are performed at a flow rate of 30 μL per min (injection time 120 s, dissociation time 360 s). The sensor surface is regenerated by consecutive injections of 0.35 M EDTA pH 8.0 with 0.1 mg/mL trypsin, 0.5 M imidazole and 45% DMSO (60 s, 15 μL per min).


Cell Assay: S63845 is a highly selective and potent MCL1 inhibitor. S63845 bound human MCL1 with KD value of 0.19 nM. S63845 was approximately 1,000-fold more potent in killing MCL1-dependent H929 multiple myeloma cells than MCL1 inhibitor A-1210477. S63845 also induced caspase-dependent phosphatidyl-serine exposure, PARP cleavage and cytochrome c release from mitochondria. In HeLa cells, S63845 disrupted binding of BAK and BAX to MCL1. S63845 killed cancer cells through activation of the BAX/BAK-dependent mitochondrial apoptotic pathway by direct inhibition of MCL1.

In VivoIntravenously injected (i.v.) S63845 exerted dose-dependent anti-tumour activity in human multiple myeloma (H929 and AMO1) xenografts in immunocompromised mice, with maximal tumour growth inhibition (TGImax) of 114% in the AMO1 model and 103% in the H929 model. S63845 (25 mg/kg) induced complete regression in 7 out of 8 of the mice at 100 days after treatment in the AMO1 model. S63845 (i.v., 25 mg/kg, 5 days) cured 70% of immuno-competent C57BL/6 mice bearing Eμ-Myc mouse lymphomas, with no side-effects evident in normal tissues. S63845 (12.5 mg/kg) showed potent activity in the MV4-11 human AML xenograft model, with a TGImax of 86%. S63845 (25 mg/kg) resulted in completeremission in 6 out of 8 mice after 80 days.
Animal modelHuman multiple myeloma (H929 and AMO1) xenografted mice
Formulation & DosageIntravenously injected (i.v.), 25 mg/kg
ReferencesNature. 2016 Oct 27;538(7626):477-482.