Preclinical Data Support Rationale for Clinical Study
ROCKVILLE, Md., June 2 /PRNewswire-FirstCall/ -- EntreMed, Inc.(Nasdaq: ENMD), a clinical-stage pharmaceutical company developingtherapeutics for the treatment of cancer and inflammatory diseases, todayannounced the presentation of preclinical data for its Aurora A/angiogenesiskinase inhibitor, ENMD-981693, the free base of ENMD-2076. The data werepresented by Dr. Xiaojing Wang, postdoctoral fellow of EntreMed collaboratorDr. Sherif S. Farag, Division of Hematology and Oncology, Indiana UniversitySchool of Medicine, at the American Society of Clinical Oncology AnnualMeeting being held this week in Chicago, Illinois.
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ENMD-2076 free base exhibited dose-dependent cytotoxicity towards multiplemyeloma (MM) cell lines, and was shown to induce cell death in vitro followingrelatively short (6 hour) exposures through apoptosis via a mitochondrialpathway. Consistent with the effect of ENMD-2076 free base on severalreceptor tyrosine kinases, inhibition of phosphorylation of proteins in theoncogenic PI3-kinase/Akt pathway including p-BAD, p-FOXO1a, and p-GSK3beta wasobserved. Longer incubations of MM cells (24-48 hours) with ENMD-2076 freebase elicited increased cell death with concomitant inhibition of Aurora Aautophosphorylation, induction of cell cycle arrest, and downregulation ofcyclins A and B1. ENMD-2076, administered either on a daily or weeklyschedule, elicited complete inhibition of tumor growth towards a xenograft ofthe human myeloma cell line H929 in vivo.
ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with aunique kinase selectivity profile and multiple mechanisms of action.ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosinekinase targets in addition to Aurora A kinase and other oncogenic proteins.Aurora kinases are key regulators of mitosis (cell division), and are oftenover-expressed in human cancers. Inhibition of Aurora A has been shown toinduce cell death in preclinical multiple myeloma cell lines. In addition,ENMD-2076 is selective for the Aurora A isoform in comparison to Aurora B.
Dr. Mark R. Bray, Vice President Research at EntreMed commented on thepresentation, 'The research of Dr. Farag and his co-workers has yieldedimportant insights into the mechanism of cell death induced by ENMD-2076.These data support EntreMed's clinical rationale for this compound and providefurther validation for its potential clinical utility in hematologicalcancers, including multiple myeloma.
