This Article Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Williamson, M. J. Articles by Rolfe, M. Search for Related Content PubMed PubMed Citation Articles by Williamson, M. J. Articles by Rolfe, M.

Research Articles: Therapeutics, Targets, and Development

Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib

Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

Requests for reprints: Mark J. Williamson, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139. Phone: 617-551-7847; Fax: 617-551-8906. E-mail: mark.williamson{at}mpi.com

Abstract

Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated. [Mol Cancer Ther 2006;5(12):3052–61]

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 C.L. Reimer and A.M. Mazzola, unpublished data.

Received 4/ 4/06; revised 8/17/06; accepted 10/26/06.