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 demonstrated a statistically meaningful impact on IMPDH and other proteins that are critical to activities in cancer cells, including nucleotide biosynthesis, energy and metabolism, DNA replication, apoptosis and cell cycle control. AVN944 has been associated with cancer cell death in clinical trials. It is being investigated for the treatment of patients with advanced hematologic malignancies.
Inosine Monophosphate Dehydrogenase Inhibitor AVN944 is an orally available, synthetic small molecule with potential antineoplastic activity. AVN944 inhibits inosine monosphosphate dehydrogenase (IMPDH), an enzyme involved in the de novo synthesis of guanosine triphosphate (GTP), a purine molecule required for DNA and RNA synthesis. Inhibition of IMPDH deprives cancer cells of GTP, resulting in disruption of DNA and RNA synthesis, inhibition of cell proliferation, and the induction of apoptosis. AVN944 appears to have a selective effect on cancer cells in that deprivation of GTP in normal cells results in a temporary slowing of cell growth only. IMPDH is overexpressed in some cancer cells, particularly in hematological malignancies.

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Drug Indication
Investigated for use/treatment in cancer/tumors (unspecified), leukemia (unspecified), lymphoma (unspecified), multiple myeloma, and pancreatic cancer.

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Mechanism of Action
AVN944 inhibits IMPDH and appears to induce apoptosis. Specifically, it was found that the gene HspA1A, a marker of stress response found to correlate with depleted GTP pools in cancer cell lines, is induced within hours upon the first treatment of the drug in patients, even at the trial's lowest doses. Following continued dosing of AVN944, this marker of disease cell stress was elevated even in the absence of circulating levels of the drug between doses.

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Pharmacodynamics
IMPDH is highly upregulated in most hematological cancers and in many solid tumors. AVN944 is a biotech drug that demonstrated a statistically meaningful impact in inhibiting IMPDH and other proteins that are critical to activities in cancer cells, including nucleotide biosynthesis, energy and metabolism, DNA replication, apoptosis and cell cycle control. AVN944 has been associated with cancer cell death in clinical trials. It is being investigated for the treatment of patients with advanced hematologic malignancies.

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.)