Tasquinimod-ABR-215050-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemETasquinimodCat. No.: HY-10528CAS No.: 254964-60-8Synonyms: ABR-215050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

2、/mL (103.36 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration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，并请注意储备液的保存式和期限。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，配制前请先配制澄清的储备液，再依次添加助溶剂(为

3、保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：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 solution2. 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 solution1/3 Master of Small Mole

4、cules 您边的抑制剂师www.MedChemE3. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.15 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Tasquinimod种服抗管成剂，临床试验于治疗去势抵抗性前列腺癌的。 Tasquinimod与 HDAC4Zn2+ 结合结构域结合的Kd 值为10-30 nM。IC50 & Target HDAC410-30 nM (Kd)体外研究 Tasquinimod suppresses hypoxia induced decrease in

5、histone acetylation without lowering HDAC expressionor directly inhibiting HDAC activity. Tasquinimod binds allosterically within the regulatory Zinc domain ofHDAC4 with a Kd of 10-30 nM, which results in inhibition of co-localization of N-CoR/HDAC3, therebyinhibiting deacetylation of histones and H

6、DAC4 client transcription factors, such as HIF-1. TAMs secreteangiogenic factors like VEGF, FGF, TNF- , and TGF- when myeloid-derived suppressor cells differentiate.Tasquinimod can suppress tumor angiogenesis due to inhibition of S100A9/TLR4 dependent MDSCs tumorinfiltration and/or to inhibition of

7、HDAC4/N-CoR/HDAC3 dependent deacetylation of HIF-1 by MDSCssuppressing their differentiation into TAMs. 1. Tasquinimod, an orally active quinoline-3-carboxamide, bindswith high affinity to HDAC4 and S100A9 in cancer and infiltrating host cells within compromised tumormicroenvironment inhibiting adap

8、tive survival pathways needed for an angiogenic response 2. At 10 MTasquinimod, the TSP1 mRNA expression is elevated at 6 h and peaked after 72 h. Moreover, after 72 hexposure the TSP1 mRNA levels is already elevated at a dose of 1 M Tasquinimod, indicating thatTasquinimod-induced changes in TSP1 mR

9、NA 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 concentrations. Theup-regulation of TSP1 mRNA in LNCaP cells by Tasquinimod is manifested by an increased expression ofTSP1 protein, as shown by we

10、stern blot analysis of cell lysates prepared from cells cultured for 24 h and 72h. Accompanied by increased intracellular TSP1 protein levels are also a statistically significant (p 3.体内研究 The bioavailability and oral absorption of Tasquinimod is excellent when adult male mice (i.e., C57Bl/6J, orath

11、ymic nude mice) are given 0.1-30 mg/kg (i.e., 0.2-74 moles/kg) via gavage or the drinking water. Thepotency of Tasquinimod expressed as the daily oral dose of Tasquinimod which inhibits cancer growth by50% ranges from 0.1-1.0 mg/kg/d (i.e., 0.24-2.40 moles/kg/day) against a series (n5) of human pros

12、tatecancer xenografts in immune-deficient mice. Tasquinimod at a chronic dose of 5 mg/kg/day via the drinkingwater produces 80% inhibition (p 2. Nude mice carrying subcutaneous LNCaP tumors are treated withTasquinimod for 3 weeks. Exposure to Tasquinimod at 1 mg/kg/day and 10 mg/kg/day started on da

13、y 7 afterinoculation. There is a statistically significant dose dependent reduction in tumor weight both at 1 mg/kg/dayand 10 mg/kg/day compare to the untreated control group 28 days after inoculation (p 3.PROTOCOLCell Assay 3 Two human prostate cancer cell lines, CWR-22RH and LNCaP (ATCC) are both

14、androgen independent, but2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEremain sensitive to androgen stimulation of growth, express PSA and a mutated androgen receptor. Thehormone independent cell lines LNCaP19 and DU145 are also tested for TSP1 induction after in vitroexposure to Tasquinimod (0.1

15、-100 M). CWR-22RH, LNCaP and DU145 are grown in RPMI Medium 1640containing 10% FCS and L-Glutamine mixture, while LNCAP19 is cultured in RPMI-medium with 10%hormone free (RDCC) FCS 3.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 3Administr

16、ation 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 microcaliper twice a week throughout the experiment, and the finaltumor burden is measured by weight on the day of termination of the experiment. Distribu

17、tion of Tasquinimodat 1 mg/kg/day and 10 mg/kg/day (administered orally via the drinking water) started on day 7 afterinoculation.MCE has not independently 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 Jun 14. Methods Mol Biol. 2018;1711:351-

18、398.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Isaacs JT, et al. Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment.Cancer Res. 2013 Feb 15;73(4):1386-99.2. Isaacs JT, et al. Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumormicroenvironment. Oncotarget. 2014 Sep 30;5(18):8093-106.3. Olsson A, et al. Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the ex