TAS4464

TAS4464 selectively inhibits NAE relative to the other E1s UAE and SAE. TAS4464 treatment inhibits cullin neddylation and subsequently induces the accumulation of CRL substrates such as CDT1, p27, and phosphorylated IkBa in human cancer cell lines. Cytotoxicity profiling reveals that TAS4464 is highly potent with widespread antiproliferative activity not only for cancer cell lines, but also patient-derived tumor cells.^[1]

TAS4464 shows prolonged target inhibition in human tumor xenograft mouse models; weekly or twice a week TAS4464 administration led to prominent antitumor activity in multiple human tumor xenograft mouse models including both hematologic and solid tumors without marked weight loss.^[1]

• Cell lines

  PBMC, AML, DLBCL, SCLC cells. Patient-derived ovary and endometrial cells. Hepatocytes.

• Concentrations

  1 nM, 10 nM, 100 nM, 1000 nM

• Incubation Time

  24 h, 72 h, 6 days

• Method

  PBMC, AML, DLBCL, and SCLC cells are treated with TAS4464 for 72 hours, after which viability is measured. Patient-derived ovary and endometrial cells are maintained in low-attachment plates and treated with TAS4464 or chemotherapeutic agents for 6 days. Cell viability is then measured by using the CellTiter-Glo 3D Cell Viability Assay. Hepatocytes are cultured in Cell-able plate for 10 days and then treated with TAS4464 for 24 hours, after which viability is measured by using CellTiter-Glo 3D Cell Viability Assay.

• Animal Models

  6-week-old female NOD-SCID mice

• Dosages

  100 mg/kg, 75 mg/kg

• Administration

  IV