Back to products

Browse products

Approved anticancer agents

Anticancer agents in trials

Anticancer agents in preclinical trials

Anticancer molecular libraries

MedKoo product information:

AVN-944

AVN-944 (VX-944) 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. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer: Vertex Pharmaceuticals.

AVN944, a biphenyl carbamate with 1 cyano group (C25H27N5O5, molecular weight, 477.5 Daltons), is a highly selective, nonnucleoside, uncompetitive inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH, EC1.1.1.205).  AVN944 is well tolerated within the 25- to 250-mg range of doses tested when administered orally to healthy male study participants. The pharmacodynamic profile, which demonstrates extended suppression of the intracellular GTP pools, suggests that AVN944 could disrupt cellular proliferation and may have anticancer effects. The results, therefore, provide a scientific rationale for the development of AVN944 as an oral anticancer agent. Clinical trials of AVN944 in cancer patients on a twice-a-day dosing schedule are ongoing.  (source: J Clin Pharmacol. 2009 Jan;49(1):30-8. )

Highlights on recent research results using AVN-944

Data published in 2009

A phase I dose-ranging study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of AVN944. ( Hamilton JM, Harding MW, Genna T, Bol DK. J Clin Pharmacol. 2009 Jan;49(1):30-8. Epub 2008 Oct 29.). A phase I study of AVN944, an inosine monophosphate dehydrogenase (IMPDH) inhibitor, was carried out to assess its safety, tolerability, pharmacokinetics, and pharmacodynamics. Healthy male volunteers (N = 25) participated in this double-blind, randomized, placebo-controlled trial. Sixteen received oral doses ranging from 25 to 250 mg on 3 separate occasions at intervals of 3 or 6 days after overnight fasting. Six participants received two 100-mg doses, and 2 participants received 2 placebo doses, one with food and the other after fasting overnight. Clinical and laboratory parameters, including excretion of AVN944 and thiocyanate and IMPDH inhibition, were made at intervals for 48 hours postdosing. There were 13 mild and 2 moderate but no serious adverse events. One mild and 1 moderate event could be treatment related. AVN944 disappeared rapidly from plasma, but clearance decreased at doses > 50 mg. Food reduced absorption, with a geometric mean Cmax ratio of 33% and a geometric mean AUC0-infinity ratio of 44%. Urinary excretion was negligible. AVN944 doses > 100 mg showed definite IMPDH inhibition lasting at least 4 to 6 hours. AVN944, when administered orally to healthy volunteers, is well tolerated, absorbs better with fasting, and exhibits a pharmacodynamic profile that suggests potential for significant anticancer activity.

Data published in 2008

Antiproliferative effects of AVN944 in prostate cancer cells. (Floryk D, Thompson TC. Int J Cancer. 2008 Nov 15;123(10):2294-302.).  AVN944 is a new, specific, noncompetitive IMPDH inhibitor. In this study, we investigated the effects of IMPDH inhibitor AVN944 on LNCaP, CWR22Rv1, DU145 and PC-3 human prostate cancer cells. AVN944 inhibited proliferation of these 4 prostate cancer cell lines and was associated with cell cycle G1 arrest of LNCaP cells and S-phase block of androgen-independent CWR22Rv1, DU145 and PC-3 cells. 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. In summary, AVN944 inhibited the growth of human prostate cancer cells by inducing cell cycle arrest, cell death as well as differentiation. AVN944 is a novel, promising therapeutic agent that might be combined with other agents for treatment of human prostate cancer.

1. β-Adrenergic receptor agonists for the treatment of B-cell proliferative disorders By Rickles, Richard; Lee, Margaret S. From PCT Int. Appl. (2009), WO 2009151569 A2 20091217.

2. A phase I dose-ranging study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of AVN944, an IMPDH inhibitor, in healthy male volunteers By Hamilton, J. Michael; Harding, Matthew W.; Genna, Thomas; Bol, David K. From Journal of Clinical Pharmacology (2009), 49(1), 30-38.

3. Combinations for the treatment of B-cell proliferative disorders By Rickles, Richard; Pierce, Laura; Lee, Margaret S. From PCT Int. Appl. (2009), WO 2009011897 A1 20090122.

4. Depletion of guanine nucleotides leads to the Mdm2-dependent proteasomal degradation of nucleostemin By Huang, Min; Itahana, Koji; Zhang, Yanping; Mitchell, Beverly S. From Cancer Research (2009), 69(7), 3004-3012.

5. Gateways to clinical trials By Tomillero A; Moral M A From Methods and findings in experimental and clinical pharmacology (2009), 31(2), 107-46.

6. Use of adenosine A2A receptor agonists and phosphodiesterase (PDE) inhibitors for the treatment of B-cell proliferative disorders, and combinations with other agents By Rickles, Richard; Lee, Margaret S. From PCT Int. Appl. (2009), WO 2009011893 A2 20090122.

7. Antiproliferative effects of AVN944, a novel inosine 5-monophosphate dehydrogenase inhibitor, in prostate cancer cells By Floryk, Daniel; Thompson, Timothy C. From International Journal of Cancer (2008), 123(10), 2294-2302.

8. Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption By Huang, Min; Ji, Yanshan; Itahana, Koji; Zhang, Yanping; Mitchell, Beverly From Leukemia Research (2008), 32(1), 131-141.

9. Recent development of IMP dehydrogenase inhibitors for the treatment of cancer By Chen, Liqiang; Pankiewicz, Krzysztof W. From Current Opinion in Drug Discovery & Development (2007), 10(4), 403-412.