title: ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action.
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.
authors.affiliation: Entremed Inc., 101 College Street, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Fletcher
authors.forename: Richard D
authors.initials: RD
authors.lastname: Brokx
authors.forename: Trisha A
authors.initials: TA
authors.lastname: Denny
authors.forename: Todd A
authors.initials: TA
authors.lastname: Hembrough
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Plum
authors.forename: William E
authors.initials: WE
authors.lastname: Fogler
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Sidor
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C551397:ENMD 2076; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases