10058-F4

10058-F4 inhibits growth of leukemic cells and dimerization of Myc and Max. This compound induces cell-cycle arrest and apoptosis of AML cells. It arrests AML cells at G0/G1 phase, downregulates c-Myc expression and upregulated CDK inhibitors, p21 and p27. Meanwhile, this chemical induces apoptosis through activation of mitochondrial pathway shown by downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, it also induces myeloid differentiation, possibly through activation of multiple transcription factors. Similarly, this compound-induced apoptosis and differentiation could also be observed in primary AML cells. ^[1] It decreases c-Myc protein levels, inhibites proliferation of HepG2 cells likely through upregulation of cyclin-dependent kinase (cdk) inhibitor, p21WAF1 and lowers intracellular levels of [alpha]-fetoprotein (AFP). Treatment with this chemical also downregulates human telomerase reverse transcriptase (hTERT) at the transcriptional level. In addition to inhibiting the proliferation of HepG2 cells, it enhances sensitivity to conventional chemotherapeutic agents. ^[2]

Peak plasma 10058-F4 concentrations of approximately 300 μM are seen at 5 min and declined to below the detection limit at 360 min following a single iv dose. Plasma concentration versus time data are best approximated by a two-compartment, open, linear model. The highest tissue concentrations of this compound are found in fat, lung, liver, and kidney. Peak tumor concentrations of this chemical are at least tenfold lower than peak plasma concentrations. Eight metabolites of this compound are identified in plasma, liver, and kidney. The terminal half-life of this chemical is approximately 1 h, and the volume of distribution is >200 ml/kg. No significant inhibition of tumor growth is seen after i.v. treatment of mice with either 20 or 30 mg/kg this compound.^[3]

Cells, plated in 96-well plates (10⁵/mL for cell lines and 5 × 10⁵/mL for primary leukemic cells), are treated in triplicate with indicated concentrations of 10058-F4. At various time points, 20 μL 5 mg/mL MTT is added to each well. After incubation at 37°C for 3 hours, the MTT medium is removed and 100 μL DMSO lysis buffer is added. The number of viable cells is assessed by the percentage of absorbance of treated cells relative to that of solvent controls, using 570-nm wavelength on a spectrophotometer.

• https://pubmed.ncbi.nlm.nih.gov/17046567/
• https://pubmed.ncbi.nlm.nih.gov/17159602/
• https://pubmed.ncbi.nlm.nih.gov/18509642/