ENMD-2076 is a novel, orally active molecule that has been shown to have significant activity against Aurora kinases and multiple tyrosine-protein kinases, including tyrosine-protein kinase receptor FLT3, protooncogene c-Kit, vascular endothelial growth factor receptor VECFR-2, basic fibroblast growth factor FGFR-1 and FGFR-3, and tyrosine-protein kinase JAK2. ENMD-2076 has potent activity against various cultured tumor cells through multiple effects, including induction of early caspase-dependent apoptosis, modulation of the expression of anti-and proapoptotic proteins to favor cell death, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt pathway and Aurora kinase A and B, signaling through FGFR-3 and VEGFR, and induction of G 2/M cell cycle arrest. Potent antitumor activity in mice bearing cancer cell lines or human tumor xenografts, including human colorectal cancer, multiple myeloma, leukemia and breast cancer, is also observed. Phase I trials of ENMD-2076 are currently ongoing in solid tumors and hematologic malignancies, with preliminary results showing that the drug has acceptable toxicity and shows promising activity in at least ovarian and colon cancer, multiple myeloma and acute myeloid leukemia. Studies directed at better defining the spectrum of antitumor activity of ENMD-2076 and the relative importance of its apparently different mechanisms of action will allow the design of rational combinations of ENMD-2076 with other anticancer drugs in future clinical trials.
ASJC Scopus subject areas
- Pharmacology (medical)