ENMD-2076 is a novel orally active, small molecule
kinase inhibitor with a mechanism of action involving several pathways key to
tumor growth and survival: angiogenesis, proliferation, and the cell cycle.
ENMD-2076 has selective activity against the mitotic
kinase Aurora A, as well as
kinases involved in angiogenesis (VEGFRs, FGFRs).
ENMD-2076 inhibited the growth in vitro of a wide range of human solid
tumor and hematopoietic
cancer cell lines with IC(50) values ranging from 0.025 to 0.7 μmol/L.
ENMD-2076 was also shown to induce regression or complete inhibition of
tumor growth in vivo at well-tolerated doses in
tumor xenograft models derived from breast, colon,
melanoma,
leukemia, and
multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of
ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic
tyrosine kinases, VEGFR2/KDR and FGFR1 and 2.
ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in
tumor xenograft models. These results indicate that
ENMD-2076 is a well-tolerated, orally active multitarget
kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human
cancers. Several phase 1 studies involving
ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with
platinum-resistant
ovarian cancer.