The IMPDH Inhibitor VX-944 Demonstrates In Vivo Efficacy in an Aggressive Leukemia Model.
2004
VX-944 is a small molecule, orally bioavailable, specific inhibitor of inosine monophosphate dehydrogenase (IMPDH), an essential rate-limiting enzyme in de novo guanine nucleotide synthesis. We have previously shown that VX-944 has broad anti-cancer properties in vitro and that its potency is not affected by MDR pumps (Jain et al, Blood 2002, 100:572a; ibid 2003, 102: 622a). Here, we describe studies that demonstrate its oncolytic activity in blast cells derived from patients with acute myeloid leukemia (AML). We also report the efficacy of VX-944 in an aggressive murine model of myeloproliferative disease. The anti-leukemic activity of VX-944 was established both in colony formation assays and in viability assays using primary cells from AML patients. VX-944 inhibited the clonogenic proliferation of acute myeloid progenitor cells in a dose-dependent manner. The mean and median IC50 values were 218±92 and 199 nM respectively (n=8), indicating that no samples were resistant to VX-944. In another study, VX-944 reduced the viability of AML blasts from 4 additional patient samples, with IC50 values ranging from 20–200 nM. VX-944 was observed to be 3–40-fold more potent than mycophenolic acid (MPA, MMF), another IMPDH inhibitor. Importantly, genotyping of these samples revealed that VX-944 is active against cancer cells with wild type and point- or ITD-mutations in Flt3 that are implicated in approx 30% of AML patients. The anti-proliferative activity of VX-944 was at least additive, and in some patient samples, synergistic, when tested in combination with Daunorubicin, a standard chemotherapy drug for AML. To determine the therapeutic potential of VX-944 in vivo, VX-944 was tested in a leukemia model using Ba/F3 cells transduced with an activating human Flt-3 mutation injected into Balb/c mice. The anti-proliferative activity of VX-944 was first established in vitro in the cell lines used in the model. VX-944 inhibited the proliferation of the human MV-4-11 and murine Ba/F3-Flt3-ITD-dependent cell lines with IC50 values of 26 and 30 nM, respectively. In PK studies, a dose-dependent increase in Cmax and AUC values were observed in Balb/c mice. In the leukemia model, VX-944 was administered orally at 75 or 150 mg/kg BID. Doxorubicin (3 mg/kg, weekly), a standard AML therapy, and MLN518 (60 mg/kg BID), a selective Flt3 inhibitor, were administered as reference compounds. All treatments began 5 days following cell implantation. Both dose groups of VX-944 provided a significant increase in median survival time as compared with the vehicle treated group (p In conclusion, we have demonstrated both potency and efficacy of VX-944 in in vitro and in vivo leukemia models. These preclinical results support further clinical development of VX-944 for the treatment of patients with leukemias and other rapidly proliferating hematological malignancies. VX-944 may provide significant therapeutic benefit when used alone, or in combination with approved chemotherapy agents such as Daunorubicin.
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