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908112-43-6 分子结构
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4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[(1r,4r)-4-hydroxycyclohexyl]amino}benzamide

ChemBase编号:73138
分子式:C23H27F3N4O3
平均质量:464.4806896
单一同位素质量:464.2035254
SMILES和InChIs

SMILES:
c1cc(cc(c1C(=O)N)N[C@@H]1CC[C@H](CC1)O)n1nc(c2c1CC(CC2=O)(C)C)C(F)(F)F
Canonical SMILES:
O[C@@H]1CC[C@H](CC1)Nc1cc(ccc1C(=O)N)n1nc(c2c1CC(C)(C)CC2=O)C(F)(F)F
InChI:
InChI=1S/C23H27F3N4O3/c1-22(2)10-17-19(18(32)11-22)20(23(24,25)26)29-30(17)13-5-8-15(21(27)33)16(9-13)28-12-3-6-14(31)7-4-12/h5,8-9,12,14,28,31H,3-4,6-7,10-11H2,1-2H3,(H2,27,33)/t12-,14-
InChIKey:
ZFVRYNYOPQZKDG-MQMHXKEQSA-N

引用这个纪录

CBID:73138 http://www.chembase.cn/molecule-73138.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[(1r,4r)-4-hydroxycyclohexyl]amino}benzamide
IUPAC传统名
4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-5,7-dihydroindazol-1-yl]-2-{[(1r,4r)-4-hydroxycyclohexyl]amino}benzamide
别名
SNX-2112
CAS号
908112-43-6
PubChem SID
162038058
PubChem CID
24772860

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S2639 external link 加入购物车 请登录
数据来源 数据ID
PubChem 24772860 external link

理论计算性质

理论计算性质

JChem
Acid pKa 14.91008  质子受体
质子供体 LogD (pH = 5.5) 3.3666396 
LogD (pH = 7.4) 3.367758  Log P 3.3677723 
摩尔折射率 119.3012 cm3 极化性 43.813786 Å3
极化表面积 110.24 Å2 可自由旋转的化学键
里宾斯基五规则 true 

分子性质

分子性质

安全信息 药理学性质 产品相关信息 生物活性(PubChem)
保存条件
-20°C expand 查看数据来源
作用靶点
HSP-90 expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals
Selleck Chemicals -  S2639 external link
Biological Activity
Description SNX-2112 selectively binds to the ATP pocket of HSP90α and HSP90β with Ka of 30 nM and 30 nM, respectively.
Targets HSP90α HSP90β
IC50 30 nM (Ka) 30 nM (Ka) [1]
In Vitro Treatment of BT-474 cells with 1 μM SNX-2112 results in down-regulation of HER2 expression within 3 to 6 hours of drug exposure with near-complete loss of HER2 expression by 10 hours. Treatment with SNX-2112 also results in a decline in total Akt expression. SNX-2112 inhibits cell proliferation with IC50 values ranging from 10 to 50 nM, in BT474, SKBR-3, SKOV-3, MDA-468, MCF-7 and H1650 cancer cells. And these antiproliferative effects are associated with hypophosphorylation of Rb, arrest of G1 and modest levels of apotosis. [1] SNX-2112 competitively binds to the N-terminal adenosine triphosphate binding site of Hsp90. SNX-2112 induces apoptosis via caspase-8, -9, -3, and poly (ADPribose) polymerase cleavage. SNX-2112 inhibits cytokine-inducedAkt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. [2] Cell lines (eight cell lines from osteosarcoma, neuroblastoma, hepatoblastoma, and ymphoma) studied demonstrates sensitivity to SNX-2112 with IC50 values ranging from 10-100?nM. A higher dose (70?nM) exhibits a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of Akt1 and C-Raf are markedly reduced over time along with an increase in PARP cleavage. [3] A recent research indicates NX-2112 induces autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and utophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent. [4]
In Vivo SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model and blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis. [2]
Clinical Trials
Features
Combination Therapy
Description SNX-2112 demonstrates synergistic anti-cancer activity with Cisplatin. [3]
Protocol
Kinase Assay [1]
ATP Displacement Assay For the protein affinity –displacement assay, a purine-based affinity resin is generated by incubating ATP-linked Sepharose with Jurkat cell lysate (flash frozen and homogenized in saline) at 4 °C. This is then incubated with SNX-2112 for 90 minutes. Proteins eluted by drug are then resolved by SDS-PAGE, visualized with silver staining, and excised from the gel for MS-based identification. Briefly, after destaining and trypsin digestion, peptides are extracted with μC18 ZipTips and then eluted and spotted directly to a conventional stainless steel matrix-assisted laser desorption/ionization target with a saturated solution of α-cyano-4- hydroxycinnamic acid in 50% acetonitrile, 0.15% formic acid. Mass spectra are then acquired using a MALDI-TOF/TOF 4700 Proteomics Analyzer. MS spectra are acquired (1,000 shots per spectrum), and the three peaks from each with the greatest signal-to-noise ratio are automatically submitted for tandem MS analysis (3000 shots per spectrum). The collision energy is 1keV. Air is used as the collision gas. Protein identification is done from the MS and tandem MS data using GPS Explorer software with the integrated Mascot database search engine.
Cell Assay [1]
Cell Lines BT474, SKBR-3, SKOV-3, MDA-468, MCF-7 and H1650 cancer cells
Concentrations 0-500 nM
Incubation Time 24 hours
Methods Cell viability is determined by seeding 2-5 × 103 cells per well in 96- well plates and treating with SNX-2112 24 hours after plating in complete medium (200 μL). Each drug concentration is tested in eight wells. Cells are assayed using the Alamar blue viability test after a 96-h incubation. Flow cytometry is done using nuclei stained with ethidium bromide and isolated via the Nusse protocol
Animal Study [2]
Animal Models 5 × 106 MM.1S cells are inoculated subcutaneously in the Fox Chase SCID mice (6-7 weeks old).
Formulation SNX-5422 is dissolved in 1% carboxy methylcellulose/0.5% Tween 80 at 10 mg/mL and stored at 4 °C for in vivo study.
Doses 20 or 40 mg/kg
Administration SNX-5422 is administered orally 3 times per week, total 3 weeks.
References
[1] Chandarlapaty S, et al, Clin Cancer Res, 2008, 14(1), 240-248.
[2] Okawa Y, et al, Blood, 2009, 113(4), 846-855.
[3] Chinn DC, et al, Pediatr Blood Cancer, 2012, 58(6), 885-890.
[4] Liu KS, et al, Cancer Lett, 2012, 318(2), 180-188.

参考文献

参考文献

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