Asciminib-ABL001-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAsciminibCat. No.: HY-104010CAS No.: 1492952-76-7Synonyms: ABL001分式: CHClFNO分量: 449.84作靶點(diǎn): Bcr-Abl作通路: Protein Tyrosine Kinase/RTK儲(chǔ)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(shí)驗(yàn) DMSO : 100 mg/mL (

2、222.30 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 2.2230 mL 11.1151 mL 22.2301 mL5 mM 0.4446 mL 2.2230 mL 4.4460 mL10 mM 0.2223 mL 1.1115 mL 2.2230 mL請(qǐng)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(chǔ)備液，并請(qǐng)注意儲(chǔ)備液的保存式和期限。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥式選擇適當(dāng)?shù)娜芙獍?，配制前?qǐng)先配制澄的儲(chǔ)備液，再依次添加助溶劑(為保證實(shí)驗(yàn)結(jié)果

3、的可靠性，體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.56 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.56 mM); Clear solution1/3 Master of Small Molecules 您

4、邊的抑制劑師www.MedChemE3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.56 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Asciminib (ABL001)種有效和選擇性的變構(gòu) Bcr-Abl 抑制劑；抑制Ba/F3細(xì)胞長(zhǎng)的IC50值為0.25 nM。體外研究 Asciminib binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinaseconformatio

5、n. NMR and biophysical studies confirm that asciminib binds potently (dissociation constant=0.5-0.8nM) and selectively to the myristoyl pocket of ABL1 and induces the inactive C-terminal helixconformation. Asciminib binding mimics the structural consequences of myristate binding to the N terminus of

6、ABL1. Consistent with this binding site, asciminib exhibits the same non-ATP-competitive biochemicalkinetics as the BCRABL inhibitor GNF-2 but with approximately 100-fold greater potency. Asciminib lacksactivity against more than 60 kinases, including SRC, and is similarly inactive against G-protein

7、-coupledreceptors, ion channels, nuclear receptors and transporters. In BCRABL1-transformed Ba/F3 cells grownwithout IL-3, asciminib has an anti-proliferative with IC50 value of 0.25nM. In the CML blast-phase cell lineKCL-22, asciminib inhibits phosphorylation of both STAT5 (Tyr694; pSTAT5) and BCRA

8、BL1 (Tyr245;pBCRABL1) after 1h using concentrations that correlate with those required for inhibition of cell proliferation.Asciminib is selectively active against all BCRABL1 lines (IC50 value of 120nM), irrespective of thepresence of either the p210 or the p190 BCRABL1 isoform. 1.體內(nèi)研究 Asciminib is

9、 undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Single doses of 7.5, 15 and 30 mg/kg ABL001, administered to micebearing KCL- 22 xenografts, inhibits pSTAT5 (Tyr694), which return to baseline at 10, 12 and 16-20h after

10、administration of the dose, respectively. In mice implanted with KCL-22 tumors, the minimum dose ofasciminib required for complete regression is 7.5 mg/kg twice a day (BID) or 30 mg/kg once a day (QD), andis tolerated at doses up to 250 mg/kg BID. Similarly, in xenografts derived from patients, trea

11、tment with 7.5and 30 mg/kg asciminib leads to regressions that are maintained during dosing 1.PROTOCOLCell Assay 1 Ba/F3 cells are treated with a range concentration of asciminib (0-10000 nM) for 48 h. Cell proliferation ismeasured using the Britelite luciferase detection assay 1.MCE has not indepen

12、dently confirmed the accuracy of these methods. They are for reference only.Animal Mice: Asciminib efficacy in three patient-derived ALL systemic xenograft models (ALL-7015, AL-7119 andAdministration 1 AL-7155) is assessed by FACS monitoring of the percentage of CD45+ cells per live cell in blood sa

13、mplestaken at varying time points after dosing with either 7.5 mg/kg BID (group 2) or 30 mg/kg BID (group 3)asciminib for 3 weeks 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE1. Wylie AA, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017 Mar 30;543(7647):733-737.M