Imidazoacridinones Are Bifunctional Targeting Agents Active in Leukemia Cells.

C-1311 (Symadex™) is the lead compound in clinical development from a new series of agents, the imidazoacridinones. It was previously reported that C-1311 was solely a topoisomerase II (TOP2) cleavable complex inhibitor and DNA damaging agent. However, contemporary analyses of C-1311 point to alternative structural parallelisms with the molecular scaffolds now seen as common motifs in receptor tyrosine kinase (RTK) inhibitors. To investigate this mechanism of action, a kinase inhibitor screening program was initiated, first in silico by molecular similarity matching, and then in vitro against recombinant RTKs. C-1311 was identified to cluster with RTK inhibitors, especially when sunitinib is used as a molecular “seed” for pattern recognition. The statistical similarity coefficients fall in the 0.7–0.8 positive probability range, compared to 0.2–0.4 for the classical TOP2 inhibitors. C-1311 was found to selectively inhibit wild-type (WT) FLT3 and its D835Y mutant at nanomolar concentrations of 8–15 nM IC₅₀. FGFR2 was also targeted at approximately 100-fold greater IC₅₀ value of 1.2 μM. Inhibition of PDGFR, FGFR1, and KIT was observed at about 3–4 μM IC₅₀; other prominent kinases had values of greater than 10 μM. As a part of the dual mechanism reexamination, TOP2 decatenation of kDNA, DNA relaxation, and competition assays were performed to assess C-1311 interaction with TOP2. Results confirmed that C-1311 is not a cleavable complex inhibitor when compared to etoposide, suggesting that it may not be an inducer of the MLL cleavage. Additionally, the IC₅₀ of C-1311 from the decatenation assay is 44 μM compared to 3, 12, and 149 μM for mitoxantrone, daunorubicin, and merbarone, respectively. Cellular screens were performed to assess the potency of C-1311 in myeloid and lymphoid leukemia cell lines. C-1311 was equally effective in both WT FLT3 expressing (RS4;11) and mutant FLT3 expressing (MV-4–11) cell lines. The dual function of C-1311 may contribute to the potency in these cell lines. These findings warrant further investigation of C-1311 in yet unexplored indications, including other hematological malignancies.