他喹莫德作用機制 - Medchemexpress - MCE中國

1、Product Data SheetTasquinimodCat. No.: HY-10528CAS No.: 254964-60-8分式: CHFNO分量: 406.36作靶點: HDAC作通路: Cell Cycle/DNA Damage; Epigenetics儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 42 mg/mL (103.36 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 m

2、g 10 mgConcentration制備儲備液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請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；旦配成溶液，請分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在 6 個內(nèi)使，-20C 儲存時，請在 1 個內(nèi)使。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當(dāng)?shù)娜芙獍?。以下溶解案都請先按?In

3、 Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實驗結(jié)果的可靠性，澄 的儲備液可以根據(jù)儲存條件，適當(dāng)保存；體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.15 mM); Clear solution此案可獲得 2.5 mg/mL (6.15 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25

4、.0 mg/mL 的澄 DMSO 儲備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.15 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (6.15 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L

5、20% 的 SBE-CD 理鹽溶液中，混合均勻。3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.15 mM); Clear solution此案可獲得 2.5 mg/mL (6.15 mM，飽和度未知) 的澄 溶液，此案不適于實驗周 期在半個以上的實驗。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Tasquinimod種服抗管成劑，有潛于去勢抵抗性前列腺癌的研究。Tasquinimod與 HDAC4 Zn

6、2+ 結(jié)合結(jié)構(gòu)域結(jié)合的Kd 值為10-30 nM。Tasquinimod 也 種 S100A9 抑制劑。IC & Target HDAC410-30 nM (Kd)體外研究 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.戶使本產(chǎn)品發(fā)表的科研獻 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.