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Research Articles: Therapeutics, Targets, and Development

New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells

Department of Biochemistry, University of Zurich, Zurich, Switzerland

Requests for reprints: Heinz Gehring, Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Phone: 41-44-6355572; Fax: 41-44-6355907. E-mail: gehring{at}bioc.unizh.ch

Abstract

Pyridoxal 5'-phosphate (PLP)–dependent ornithine decarboxylase (ODC) is the key enzyme in polyamine synthesis. ODC is overexpressed in many tumor cells and thus a potential drug target. Here we show the design and synthesis of a coenzyme-substrate analogue as a novel precursor inhibitor of ODC. Structural analysis of the crystal structure of human ODC disclosed an additional hydrophobic pocket surrounding the -amino group of its substrate ornithine. Molecular modeling methods showed favorable interactions of the BOC-protected pyridoxyl-ornithine conjugate, termed POB, in the active site of human ODC. The synthesized and purified POB completely inhibited the activity of newly induced ODC activity at 100 µmol/L in glioma LN229 and COS7 cells. In correlation with the inhibition of ODC activity, a time-dependent inhibition of cell growth was observed in myeloma, glioma LN18 and LN229, Jurkat, COS7, and SW2 small-cell lung cancer cells if DNA synthesis and cell number were measured, but not in the nontumorigenic human aortic smooth muscle cells. POB strongly inhibited cell proliferation not only of low-grade glioma LN229 cells in a dose-dependent manner (IC₅₀ 50 µmol/L) but also of high-grade glioblastoma multiforme cells. POB is much more efficient in inhibiting proliferation of several types of tumor cells than -DL-difluoromethylornithine, the best known irreversible inhibitor of ODC. [Mol Cancer Ther 2007;6(6):1831–9]

Grant support: COST Switzerland, Action 922, grant C02.0017.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

² Calculated values were obtained from http://www.logp.com.

Received 1/19/07; revised 3/27/07; accepted 5/ 2/07.

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