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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (2779)	12/22/2006 11:21:16 AM
From: tuck	Respond to of 3044

[Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib] >>Mol Cancer Ther. 2006 Dec;5(12):3052-61. Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib. Williamson MJ, Blank JL, Bruzzese FJ, Cao Y, Daniels JS, Dick LR, Labutti J, Mazzola AM, Patil AD, Reimer CL, Solomon MS, Stirling M, Tian Y, Tsu CA, Weatherhead GS, Zhang JX, Rolfe M. Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139. mark.williamson@mpi.com. 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.<< Probably not going to show up in the pipeline chart. But, of course, further study is warranted because it's the authors' project. I believe a competitor -- I forget which one, maybe Nereus -- is developing an irreversible proteasome inhibitor. It's not necessarily a strike against ML858. However ,the long term potency issue may be. I don't know how easy it will be to fix that "intramolecular instability," in fact, I'm not even sure quite what they mean by that phrase. Whatever, the thing will require some tweaking, and I gather there are other follow-up proteasome inhibitors in the pipe with better chances. So maybe, this is one of those "keeping the resume interesting" publications. Erik, regarding those transactions . . . that is odd. A tax strategy? Where's Peter when you need him? Cheers, Tuck