Abstract
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.
Highlights
At present, a steadily growing number of small molecule and antibody kinase inhibitor drugs have entered the market for use in various colorectal, non–small cell lung, head and neck, renal, breast, and liver cancers, as well as gastrointestinal stromal tumors and chronic myeolcytic leukemia
Fifteen kinases displayed IC50 values of less than 100 nmol/L. Among these were multiple kinases involved in angiogenesis, including VEGFR2/KDR and VEGFR3, FGFR1 and FGFR2, and PDGFRa (Table 3)
The vinyl pyrimidine core of ENMD-2076 is unique amongst Aurora kinase inhibitors; it is a property of the structures of other compounds inhibiting targets such as Tie2 [31], Src and Abl [32], phosphatidylinositol 3-kinase and mTOR [33]
Summary
A steadily growing number of small molecule and antibody kinase inhibitor drugs have entered the market for use in various colorectal, non–small cell lung, head and neck, renal, breast, and liver cancers, as well as gastrointestinal stromal tumors and chronic myeolcytic leukemia. This class of agents is used both in combination regimens and as single agents [1,2,3]. Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Authors' Affiliations: 1Preclinical Sciences, EntreMed, Inc., Toronto, Ontario, Canada; 2Cell Biology, EntreMed, Inc.; and 3Expression Pathology Inc., Rockville, Maryland
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