AVN-944

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AVN-944

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CAS NO:

297730-17-7

VX-944

AVN-944 (VX-944) 是一种口服有效、选择性、非竞争性和特异性的IMPDH(肌苷一磷酸脱氢酶)抑制剂。AVN-944 是从头合成鸟嘌呤核苷酸的必要限速酶。AVN-944 也是一种沙粒病毒 RNA 合成 (arenavirus RNA synthesis) 抑制剂，可阻断沙粒病毒感染。AVN-944 具有广泛的抗癌活性，可用于多发性骨髓瘤 (MM) 和急性髓系白血病 (AML) 的研究。

生物活性

AVN-944 (VX-944) is an orally active, potent, selective, noncompetitive and specific inhibitor ofIMPDH(inosine monophosphate dehydrogenase). AVN-944 is an essential rate-limiting enzyme in de novo guanine nucleotide synthesis. AVN-944 is also an inhibitor ofarenavirusRNA synthesis, and blocksarenavirusinfection. AVN-944 has broad anti-cancer activities, and can be used for multiple myeloma (MM) and acute myeloid leukemia (AML) research^[1]^[2]^[3].

体外研究
(In Vitro)

AVN-944 (0-1 μM, 48 h) inhibits growth of human multiple myeloma (MM) cell lines in a dose-dependent manner^[1].
AVN-944 (800 nM, 0-72 h) inducesapoptosisin MM cell lines via a caspase-independent, Bax/AIF/Endo G pathway^[1].
AVN-944 (0-200 nM) enhances the cytotoxicity ofDoxorubicin(HY-15142A) andMelphalan(HY-17575)^[1].
AVN-944 inhibits the proliferation of the human MV-4-11 and murine Ba/F3-Flt3-ITD-dependent cell lines with IC₅₀values of 26 and 30 nM, respectively^[2].
AVN-944 (0-32 μM, 48 h) shows good activity against arenavirus infection at low doses (7.5 μM) with less cytotoxicity^[3].
AVN-944 (0-6.4 μM, 48 h) does not reduce the viability of peripheral blood mononuclear cells (PBMNCs)^[1].

Cell Proliferation Assay^[1]

Cell Line:	RPMI8226, MM.1S, and U266 cells
Concentration:	0, 100, 200, 300, 400, 600, 1000 nM
Incubation Time:	48 h
Result:	Significantly inhibited the growth of RPMI8226, MM.1S, and U266 cells in a dose-dependent fashion, with 50% inhibition (IC₅₀) values at 48 h of 450, 450, and 600 nM, respectively. Inhibited growth of drug-resistant cell lines, including Doxorubicin (Dox)-resistant RPMI8226-Dox40, Melphalan (Mel) resistant RPMI8226-LR5, and Dex (Dexamethasone) resistant MM.1R cells, with IC₅₀values similar to the parental drug-sensitive cell lines.

Apoptosis Analysis^[1]

Cell Line:	MM.1S and RPMI8226 cells
Concentration:	800 nM
Incubation Time:	48 and 72 h
Result:	Induced apoptosis in MM cell lines.

Western Blot Analysis^[1]

Cell Line:	MM.1S and RPMI8226 cells
Concentration:	800 nM
Incubation Time:	12, 24, 48 h
Result:	Induced modest cleavage of caspase 3, 8 and 9 in MM.1S cells and RPMI8226 cells. Markedly upregulated Bax and Bak, without significant changes in Bcl-2, Mcl-1, XIAP, and Bad. Observed translocation of mitochondrial proapoptotic proteins, apoptosis-inducing factor (AIF) and endonuclease G (Endo G) to cytosolic fractions.

Cell Cytotoxicity Assay^[1]

Cell Line:	MM.1S cells, MM.1S cells cultured with BMSCs
Concentration:	0, 50, 200 nM
Incubation Time:	24 h
Result:	Enhanced the cytotoxicity of of Doxorubicin and Melphalan in MM.1S cells. Additive effects were also observed in MM.1S cells cultured with BMSCs derived from MM patient.

体内研究
(In Vivo)

AVN-944 (0-150 mg/kg, Orally, twice daily) significantly increases the median survival time of leukemia model mice^[2].

Animal Model:	Balb/c mice (leukemia model, using Ba/F3 cells transduced with an activating human Flt-3 mutation injected into mice)^[2]
Dosage:	75 or 150 mg/kg
Administration:	Orally, twice daily
Result:	Provided a significant increase in median survival time. Three of the 12 mice treated with 150 mg/kg AVN-944 were still alive on Day 35 when the study was terminated.

Clinical Trial

分子量

477.51

性状

Solid

Formula

C₂₅H₂₇N₅O₅

CAS 号

297730-17-7

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

溶解性数据

In Vitro:

DMSO : 100 mg/mL(209.42 mM;Need ultrasonic)

配制储备液

浓度溶剂体积质量

1 mg

5 mg

10 mg

1 mM	2.0942 mL	10.4710 mL	20.9420 mL
5 mM	0.4188 mL	2.0942 mL	4.1884 mL
10 mM	0.2094 mL	1.0471 mL	2.0942 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；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。

In Vivo:

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方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，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

1.
请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline
Solubility: ≥ 2.5 mg/mL (5.24 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (5.24 mM，饱和度未知) 的澄清溶液。
以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。
将 0.9 g 氯化钠，完全溶解于 100 mL ddH2O 中，得到澄清透明的生理盐水溶液
2.
请依序添加每种溶剂： 10% DMSO 90%corn oil
Solubility: ≥ 2.5 mg/mL (5.24 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (5.24 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。
以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

*以上所有助溶剂都可在本网站选购。