In a dose-dependent manner, AVN-944 (0-1 μM, 48 hours) suppresses the growth of human multiple myeloma (MM) cell lines [1]. AVN-944 (800 nM, 0-72 hours) induces apoptosis in MM cell lines through the caspase-independent Bax/AIF/Endo G pathway [1]. Melphalan and doxorubicin are more cytotoxic when AVN-944 (0-200 nM) is added [1]. AVN-944 inhibits the proliferation of human MV-4-11 and murine Ba/F3-Flt3-ITD-dependent cell lines with IC50 values of 26 and 30 nM respectively [2]. AVN-944 (0-32 μM, 48 h) exhibits good activity against arenavirus infection at low doses (7.5 μM) with less cytotoxicity [3]. AVN-944 (0-6.4 μM, 48 hours) does not reduce peripheral blood mononuclear cell (PBNC) viability [1]. Cell proliferation experiment [1]

AVN-944 (0-150 mg/kg, orally, twice daily) considerably prolongs the median life time of leukemia model mice [2].

Cell proliferation experiment [1]
Cell Types: RPMI8226, MM.1S, U266 Cell
Tested Concentrations: 0, 100, 200, 300, 400, 600, 1000 nM
Incubation Duration: 48 h
Experimental Results: Dramatically inhibited the growth of RPMI8226 and MM. Acts in a dose-dependent manner on 1S and U266 cells with 50% inhibition (IC50) values of 450, 450 and 600 nM at 48 hrs (hours), respectively. Inhibits the 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 IC50 values similar to Parental drug-sensitive cell-like cell lines.

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Apoptosis analysis [1]
Cell Types: MM.1S and RPMI8226 Cell
Tested Concentrations: 800 nM
Incubation Duration: 48 and 72 hrs (hours)
Experimental Results: Induction of apoptosis in MM cell lines.

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Western Blot Analysis[1]
Cell Types: MM.1S and RPMI8226 Cell
Tested Concentrations: 800 nM
Incubation Duration: 12, 24, 48 hrs (hours)
Experimental Results: Moderate cleavage of caspases 3, 8 and 9 was induced in MM.1S cells and RPMI8226 cells. Bax and Ba

Animal/Disease Models: Balb/c mouse (leukemia model using Ba/F3 cells transduced with activated human Flt-3 mutation injected into mice) [2]
Doses: 75 or 150 mg/kg
Route of Administration: Oral , twice (two times) daily
Experimental Results: provided a significant increase in median survival time. When the study was terminated, 3 of 12 mice treated with 150 mg/kg AVN-944 were still alive at day 35.

[1]. Inosine-5'-monophosphate dehydrogenase: regulation of expression and role in cellular proliferation and T lymphocyte activation. Prog Nucleic Acid Res Mol Biol. 1998;61:181-209.

[2]. Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption. Leuk Res. 2008 Jan;32(1):131-41.

[3]. Antiproliferative effects of AVN944, a novel inosine 5-monophosphate dehydrogenase inhibitor, in prostate cancer cells. Int J Cancer. 2008 Nov 15;123(10):2294-302.

AVN944 is a biotech drug that has been shown to have statistically significant effects on IMPDH and other proteins crucial to cancer cell activity, including nucleotide biosynthesis, energy metabolism, DNA replication, apoptosis, and cell cycle regulation. Clinical trials have demonstrated that AVN944 is associated with cancer cell death. Its efficacy in treating patients with advanced hematologic malignancies is currently under investigation.
AVN944, an inosine monophosphate dehydrogenase inhibitor, is an orally synthesized small molecule drug with potential antitumor activity. AVN944 inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the de novo synthesis of guanosine triphosphate (GTP), a purine molecule essential for DNA and RNA synthesis. Inhibition of IMPDH leads to a lack of GTP in cancer cells, resulting in impaired DNA and RNA synthesis, inhibited cell proliferation, and induced apoptosis. AVN944 appears to have a selective effect on cancer cells; GTP deficiency in normal cells only leads to a temporary slowdown in cell growth. IMPDH is overexpressed in certain cancer cells, particularly in hematologic malignancies. Drug Indications It has been investigated for the treatment of cancer/tumor (unspecified), leukemia (unspecified), lymphoma (unspecified), multiple myeloma, and pancreatic cancer. Mechanism of Action AVN944 inhibits IMPDH and appears to induce apoptosis. Specifically, studies have found that even at the lowest doses in trials, the stress response marker HspA1A gene (which is associated with GTP pool depletion in cancer cell lines) is induced within hours of the first dose. Following continued administration of AVN944, this disease-related cellular stress marker remains elevated even with zero circulating drug levels between doses. Pharmacodynamics IMPDH is highly upregulated in most hematologic malignancies and many solid tumors. AVN944 is a biotech drug that has been shown to have statistically significant effects in inhibiting IMPDH and other proteins crucial to cancer cell activity, including nucleotide biosynthesis, energy metabolism, DNA replication, apoptosis, and cell cycle regulation. Clinical trials have demonstrated that AVN944 is associated with cancer cell death. Its efficacy in treating patients with advanced hematologic malignancies is currently under investigation.

C25H27N5O5

477.512

477.201

297730-17-7

9918559

White to off-white solid powder

5.764

3

7

10

35

743

2

O=C(O[C@@H](CC#N)CC)N[C@H](C1=CC=CC(NC(NC2=CC=C(C3=CN=CO3)C(OC)=C2)=O)=C1)C

GYCPCOJTCINIFZ-OXJNMPFZSA-N

InChI=1S/C25H27N5O5/c1-4-20(10-11-26)35-25(32)28-16(2)17-6-5-7-18(12-17)29-24(31)30-19-8-9-21(22(13-19)33-3)23-14-27-15-34-23/h5-9,12-16,20H,4,10H2,1-3H3,(H,28,32)(H2,29,30,31)/t16-,20+/m0/s1

[(2R)-1-cyanobutan-2-yl] N-[(1S)-1-[3-[[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]carbamoylamino]phenyl]ethyl]carbamate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~209.42 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)