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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"""
AVN944 also induced differentiation of androgen-independent prostate cancer cells as indicated by
Target:
What is the solubility of AVN944 (AVN-944
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