GNE-781 - CBP 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEGNE-781Cat. No.: HY-108696CAS No.: 1936422-33-1分式: CHFNO分量: 525.59作靶點(diǎn): Epigenetic Reader Domain; Histone Acetyltransferase作通路: Epigenetics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

2、 mg/mL (190.26 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 1.9026 mL 9.5131 mL 19.0262 mL5 mM 0.3805 mL 1.9026 mL 3.8052 mL10 mM 0.1903 mL 0.9513 mL 1.9026 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)先配制澄清的儲(chǔ)備液，再依次添加助溶劑(為保證實(shí)驗(yàn)結(jié)果的可靠性，體內(nèi)實(shí)驗(yàn)的作液，建

3、議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲(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: 1.67 mg/mL (3.18 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 1.67 mg/mL (3.18 mM); Clear solution3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubil

4、ity: 1.67 mg/mL (3.18 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEBIOLOGICAL ACTIVITY物活性 GNE-781種效的選擇性 CBP 抑制劑，在 TR-FRET 實(shí)驗(yàn)中 IC50 為 0.94 nM。GNE-781 還抑制 BRET 和BRD4 (1)，IC50 分別為 6.2 nM 和 5100 nM。IC50 & Target IC50: 0.94 nM (CBP), 6.2 nM (BRET), 5100 nM (BRD4(1) 1體外研究 GNE-781 is

5、 a highly advanced potent and selective bromodomain inhibitor of cyclic adenosinemonophosphate response element binding protein, binding protein (CBP). GNE-781 reduces FOXP3(forkhead box P3) transcript levels. Examination of a subset of bromodomains reveals that GNE-781 isexquisitely selective for C

6、BP/P300 and is remarkably selective for CBP (5425-fold) and P300 (4250-fold).GNE-781 demonstrates an appropriate balance of cell potency, selectivity (5425-fold over BRD4(1) 1.體內(nèi)研究 GNE-781 is a highly potent and selective CBP inhibitor that is efficacious in a MOLM-16 AML xenograftmodel. GNE-781 dis

7、plays antitumor activity in an AML tumor model and is also shown to decrease Foxp3transcript levels in a dose dependent manner.GNE-781 shows moderate to low clearance in vivo in allspecies evaluated, with acceptable oral bioavailability. The effect of GNE-781 is determined in an in vivoPK/PD experim

8、ent using a MOLM-16 (adult AML cell line) xenograft mouse model. Single doses of GNE-781are given at dose levels between 3 and 30 mg/kg in MOLM-16 tumor-bearing animals, and samples arecollected at time points covering 2-24 h. Tumor RNA is generated and used to assess MYC transcript byquantitative R

9、T-PCR relative to vehicle-treated animals. Suppression of MYC is observed at doses as low as3 mg/kg at 2 and 8 h, with maximal suppression observed at 10 and 30 mg/kg at 2 h (87% and 88%inhibition, respectively). To evaluate the in vivo efficacy of GNE-781, MOLM-16 AML xenografts areestablished in S

10、CID beige mice. Upon tumor establishment, dosing of GNE-781 is initiated with po doses of3-30 mg/kg, twice daily (BID). Single-agent efficacy is observed at all doses, as evidenced by inhibition ofMOLM-16 tumor growth. Tumor growth inhibition (%TGI) is 73%, 71%, and 89% at 3, 10, and 30 mg/kg,respec

11、tively. All doses of GNE-781 are well tolerated over the 21-day dosing window, with a maximal bodyweight loss of 3.7% 1.PROTOCOLAnimal Mice 1Administration 1 Twelve female CD-1 mice are used. All animals are 6-9 weeks old at the time of study and weighed between20 and 35 g. Animals (n=3 per dosing r

12、oute) are dosed with 10 or GNE-781 at 1 mg/kg iv (in propyl ethyleneglycol 400 (35% v/v) and water (65% v/v) or 5 mg/kg po (suspended in 0.5% w/v methylcellulose, 0.2% w/vTween 80). Food and water are available ad libitum to all animals. Serial blood samples (15 L) are collectedby tail nick at 0.033

13、, 0.083, 0.25, 0.5, 1, 3, 8, and 24 h after the intravenous administration and 0.083, 0.25,0.5, 1, 3, 8, and 24 h after the oral administration. All blood samples are diluted with 60 L of watercontaining 1.7 mg/mL EDTA and kept at -80 C until analysis 1.Rats 1Twelve male Sprague-Dawley rats are used

14、. All animals are 6-9 weeks old at the time of study and weighedbetween 200 and 300 g. Animals (n=3 per dosing route) are dosed with 10 or GNE-781 at 1 mg/kg iv (in2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEpropyl ethylene glycol 400 (35% v/v) and water (65% v/v) or 5 mg/kg po (suspended in 0.

15、5% w/vmethylcellulose, 0.2% w/v Tween 80). Food and water are available ad libitum to animals in the iv groups.Animals in po groups are fasted overnight and food withheld until 4 h postdose. Approximately 250 L ofblood are collected via the catheter at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h a

16、fter the intravenous or oraladministration. All blood samples are collected into tubes containing 5 L of 0.5 M K2EDTA and processedfor plasma. Samples are centrifuged (2500g for 15 min at 4C) within 1 h of collection, and plasma samplesare kept at -80 C until analysis 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Romero FA, et al. GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine MonophosphateResponse Element Binding Protein, Binding Pro