AVN944 (VX-944, AVN-944)

Catalog No.	APIM050292
Product Name	AVN944 (VX-944, AVN-944)

Description

APIM050292: AVN-944 (VX-944, AVN944), an Orally Available, Uncompetitive Small Molecule Inhibitor of Inosine Monophosphate Dehydrogenase (IMPDH)

CAS No.: 297730-17-7
IUPAC/Chemical Name: (R)-1-cyanobutan-2-yl ((S)-1-(3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate
Molecular Formula: C₂₅H₂₇N₅O₅•0.35H₂O
Molecular Weight: 483.8
Purity: >99% chem and stereomerical purity (HPLC and Chiral HPLC at 214 and 254 nm)
QC: HPLC-MS, ¹HNMR, Chiral HPLC and Quantitative Elemental Analysis
Solubility: Soluble in DMSO
Storage: Store at 0 °C (short term), -20 °C (long term), Desiccated
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

Multiple myeloma (MM) remains incurable despite conventional therapies including high-dose chemotherapy with stem cell support. Importantly, novel agents like thalidomide, the immunomodulatory drug Revlimid, and the proteasome inhibitor bortezomib can achieve responses in patients with relapsed and refractory MM, and are now under evaluation as treatment for patients earlier in their disease course. Nonetheless, there remains an urgent need for the development of new therapeutic strategies for MM treatment.

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme required for the de novo synthesis of guanine nucleotides from IMP. There are two IMPDH isoforms in mammalian cells: type I is constitutively expressed in most cell types, and catalytically similar type II is activated in proliferating cells. Gene expression of IMPDH type II is elevated in patient MM cells compared with normal control plasma cells. Conversely, inhibition of IMPDH induces depletion of guanine nucleotide pools, followed by decreased DNA and RNA synthesis. Recently, IMPDH has been shown to bind nucleic acids in vitro and in vivo, suggesting that it may have a direct role in replication and transcription. IMPDH inhibitors induce cell-cycle arrest and decrease T- and B-cell responses effectively, both in vitro and in vivo. Consequently, they have been evaluated primarily as immunosuppressive rather than anticancer therapies. Specifically, the IMPDH inhibitors benzamide riboside (BR) and mycophenolic acid (MPA) were found to induce growth inhibition, but not cytotoxicity, in the panel of 60 cancer cell lines derived from hematological and solid tumors at the National Cancer Institute. More recently, however, BR and MPA have been shown to induce apoptosis in selected cancer cells. Although activation of caspases and inhibition of PARP have been reported as possible mediators of apoptosis triggered by MPA and BR, their mechanisms of action are not fully characterized. MPA and tiazofurin, another IMPDH inhibitor, have been evaluated in cancer animal models, as well as in clinical trials, for the treatment of leukemia and CML, respectively. Both compounds showed some objective responses, but gastrointestinal intolerance (MPA) or neurotoxicity (tiazofurin) has limited further investigation. Hence, evaluation of more selective and well-tolerated IMPDH inhibitors is needed to determine the therapeutic potential of this approach in the treatment of malignancy.[1]

AVN-944 (AVN944, VX-944) (CAS No. 297730-17-7) is a selective, noncompetitive inhibitor of the enzyme directed against human IMPDH with Ki of 6-10 nM for IMPDH1/IMPDH2. IC₅₀ value: 6-10 nM (Ki).[2]

AVN-944 strikingly inhibit RNA synthesis within 2 h of exposure. Depletion of guanine nucleotides by MPA and AVN-944 also causes an early and near-complete reduction in levels of the 45S precursor rRNA synthesis and the concomitant translocation of nucleolar proteins including nucleolin, nucleophosmin, and nucleostemin from the nucleolus to the nucleoplasm.[3]

AVN944 induced caspase-dependentand caspase-independent cell death in LNCaP, CWR22Rv1, and DU145 cells. AVN944 induced expression of p53-target proteins Bok, Bax and Noxa in androgen-responsive cell lines and suppressed expression of survivin in prostate cancer cells regardless of their androgen sensitivity.

AVN944 also induced differentiation of androgen-independent prostate cancer cells as indicated by morphological changes and increased expression of genes coding for prostasomal proteins, keratins and other proteins, including tumor suppressor genes MIG-6 and NDRG1.
AVN944-differentiated androgen-independent DU145 and PC-3 cells are sensitized to TRAIL-induced apoptosis as demonstrated by induction of caspases and PARP cleavage.[4]

Target: IMPDH, IMPDH1, IMPDH2

What is the solubility of AVN944 (AVN-944, VX-944) in vitro?
100 mg/mL in DMSO (Need ultrasonic)

What is the solubility of AVN944 (AVN-944, VX-944) in vivo?
1. Solvent: DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order; solubility ≥ 2.5mg/mL.
2. DMSO and corn oil
Please add 10% DMSO and 90% corn oil in order, solubility ≥ 2.5 mg/mL.

Reference:
[1]. Floryk D. et al. “Novel Inosine Monophosphate Dehydrogenase Inhibitor VX-944 Induces Apoptosis in Multiple Myeloma Cells Primarily via Caspase-Independent AIF/Endo G Pathway”, Oncogene 2005, 24, 5888–5896.
[2]. Zimmermann, A. G. et al. “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.
[3]. Huang, M. et al. “Guanine Nucleotide Depletion Inhibits Pre-ribosomal RNA Synthesis and Causes Nucleolar Disruption”, Leuk. Res. 2008, 32, 131-141.
[4]. Floryk D. et al. “Antiproliferative effects of AVN944, a novel inosine 5-monophosphate dehydrogenase inhibitor, in prostate cancer cells”, Int. J. Cancer 2008, 123, 2294-2302.
[5]. Floryk D. et al. “The IMPDH Inhibitor VX-944 Demonstrates In Vivo Efficacy in an Aggressive Leukemia Model”, Blood 2004, 104, 2530.

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