他喹莫德作用机制 - Medchemexpress - MCE中国

1、Product Data SheetTasquinimodCat. No.: HY-10528CAS No.: 254964-60-8分式: CHFNO分量: 406.36作靶点: HDAC作通路: Cell Cycle/DNA Damage; Epigenetics储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 42 mg/mL (103.36 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 m

2、g 10 mgConcentration制备储备液1 mM 2.4609 mL 12.3044 mL 24.6087 mL5 mM 0.4922 mL 2.4609 mL 4.9217 mL10 mM 0.2461 mL 1.2304 mL 2.4609 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 储存时，请在 6 个内使，-20C 储存时，请在 1 个内使。体内实验请根据您的实验动物和给药式选择适当的溶解案。以下溶解案都请先按照 In

3、 Vitro 式配制澄清的储备液，再依次添加助溶剂：为保证实验结果的可靠性，澄 的储备液可以根据储存条件，适当保存；体内实验的作液，建议您现现配，当天使； 以下溶剂前显的百分 指该溶剂在您配制终溶液中的体积占；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的式助溶1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.15 mM); Clear solution此案可获得 2.5 mg/mL (6.15 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 25

4、.0 mg/mL 的澄 DMSO 储备液加到 400 L PEG300 中，混合均匀；向上述体系中加50 L Tween-80，混合均匀；然后继续加 450 L 理盐定容 1 mL。2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.15 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 2.5 mg/mL (6.15 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 900 L

5、20% 的 SBE-CD 理盐溶液中，混合均匀。3. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.15 mM); Clear solution此案可获得 2.5 mg/mL (6.15 mM，饱和度未知) 的澄 溶液，此案不适于实验周 期在半个以上的实验。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 900 L 油中，混合均匀。BIOLOGICAL ACTIVITY物活性 Tasquinimod种服抗管成剂，有潜于去势抵抗性前列腺癌的研究。Tasquinimod与 HDAC4 Zn

6、2+ 结合结构域结合的Kd 值为10-30 nM。Tasquinimod 也 种 S100A9 抑制剂。IC & Target HDAC410-30 nM (Kd)体外研究 Tasquinimod suppresses hypoxia induced decrease in histone acetylation without lowering HDAC expression ordirectly inhibiting HDAC activity. Tasquinimod binds allosterically within the regulatory Zinc domain of HD

7、AC4 with aKd of 10-30 nM, which results in inhibition of co-localization of N-CoR/HDAC3, thereby inhibiting deacetylation ofhistones and HDAC4 client transcription factors, such as HIF-1. TAMs secrete angiogenic factors like VEGF, FGF, TNF-, and TGF- when myeloid-derived suppressor cells differentia

8、te. Tasquinimod can suppress tumor angiogenesis dueto inhibition of S100A9/TLR4 dependent MDSCs tumor infiltration and/or to inhibition of HDAC4/N-CoR/HDAC3dependent deacetylation of HIF-1 by MDSCs suppressing their differentiation into TAMs.1. Tasquinimod, an orallyactive quinoline-3-carboxamide, b

9、inds with high affinity to HDAC4 and S100A9 in cancer and infiltrating host cellswithin compromised tumor microenvironment inhibiting adaptive survival pathways needed for an angiogenicresponse2. At 10 M Tasquinimod, the TSP1 mRNA expression is elevated at 6 h and peaked after 72 h. Moreover,after 7

10、2 h exposure the TSP1 mRNA levels is already elevated at a dose of 1 M Tasquinimod, indicating thatTasquinimod-induced changes in TSP1 mRNA expression occurrs in a dose range. At higher dose levels (i.e. 50-100 M) the mRNA levels decline at 72 h, indicating additional drug effects at these concentra

11、tions. The up-regulation ofTSP1 mRNA in LNCaP cells by Tasquinimod is manifested by an increased expression of TSP1 protein, as shown bywestern blot analysis of cell lysates prepared from cells cultured for 24 h and 72 h. Accompanied by increasedintracellular TSP1 protein levels are also a statistic

12、ally significant (p5) of human prostate cancer xenografts in immune-deficient mice. Tasquinimod at a chronic dose of 5 mg/kg/day via the drinking water produces 80% inhibition(p0.05) of TRAMP-C2 mouse prostate cancer growth in immune-competent syngeneic mice2. Nude mice carryingsubcutaneous LNCaP tu

13、mors are treated with Tasquinimod for 3 weeks. Exposure to Tasquinimod at 1 mg/kg/dayand 10 mg/kg/day started on day 7 after inoculation. There is a statistically significant dose dependent reduction intumor weight both at 1 mg/kg/day and 10 mg/kg/day compare to the untreated control group 28 days a

14、fterinoculation (p0.001), illustrating the anti-tumor effect of Tasquinimod3.Page 2 of 3 www.MedChemEPROTOCOLCell Assay 3 Two human prostate cancer cell lines, CWR-22RH and LNCaP (ATCC) are both androgen independent, but remainsensitive to androgen stimulation of growth, express PSA and a mutated an

15、drogen receptor. The hormoneindependent cell lines LNCaP19 and DU145 are also tested for TSP1 induction after in vitro exposure to Tasquinimod(0.1-100 M). CWR-22RH, LNCaP and DU145 are grown in RPMI Medium 1640 containing 10% FCS and L-Glutaminemixture, while LNCAP19 is cultured in RPMI-medium with

16、10% hormone free (RDCC) FCS3.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice3Administration 3 Nude BALB/c mice are used for subcutaneous implantation of human prostate tumor cells LNCaP and CWR-22RH.Tumor growth is measured with a microcalip

17、er twice a week throughout the experiment, and the final tumor burdenis measured by weight on the day of termination of the experiment. Distribution of Tasquinimod at 1 mg/kg/day and10 mg/kg/day (administered orally via the drinking water) started on day 7 after inoculation.MCE has not independently

18、 confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 J Mol Med (Berl). 2019 Aug;97(8):1183-1193. Methods Mol Biol. 2018;1711:351-398.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Isaacs JT, et al. Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment. Cancer Res. 2013Feb 15;73(4):1386-99.2.