AVN-944

Inosine monophosphate dehydrogenase 2 (IMPDH2) is implicated in survival and proliferation of cancer cells because of its role in guanine nucleotide biosynthesis. This study evaluates the efficacy of AVN944, an IMPDH2 inhibitor, as a treatment for Ewing's sarcoma, a challenging malignancy in pediatric and young adult patients. Gene expression data, as well as clinical outcomes for sarcoma patients, from The Cancer Genome Atlas (TCGA) were analyzed to determine the association between IMPDH2 expression and survival. Human Ewing's sarcoma cell lines and xenograft models were used to evaluate the cellular and in vivo effects, respectively, of AVN944. Various cellular assays, including western blotting, MTT, BrdU incorporation, and colony formation assays, were conducted to assess the impact of AVN944 on proliferation, viability, and apoptosis. IC₅₀ values were calculated from dose-response curves. Sarcoma patients with high expression of IMPDH2 showed a trend towards poorer overall survival. In vitro, AVN944 decreased the viability and proliferation of TC71 and SK-ES-1 Ewing's sarcoma cell lines significantly, and in a dose-dependent manner. The drug induced G₁ cell cycle arrest and apoptosis, as evidenced by increased expression of pro-apoptotic markers and reduced expression of cell cycle proteins. In vivo, AVN944 effectively inhibited tumor growth in xenograft models without notable toxicity. The IC₅₀ of AVN944 was approximately 0.05 μM for both TC71 and SK-ES-1 cell lines. Thus, AVN944 displays potent anti-tumor activity against Ewing's sarcoma cells both in vitro and in vivo by inhibiting IMPDH2. The inhibitor causes cell cycle arrest and apoptosis, significantly reducing tumor viability and proliferation. These findings highlight the therapeutic potential of targeting nucleotide biosynthesis pathways in Ewing's sarcoma, suggesting that AVN944 could be a valuable addition to existing treatment protocols. Further clinical investigations are recommended to validate these preclinical outcomes and to explore integration of AVN944 into treatment regimens for Ewing's sarcoma.