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

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]

Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells

“…Both NPI-0052 and bortezomib have been reported to exhibit time and concentration-dependent inhibition of the proteasome in vitro based on their different kinetics and pharmacologic profiles (58). With respect to the efficacy of each agent to induce tumor cell sensitization to TRAIL, bortezomib has been shown to be effective at concentrations ranging from 0.5 M up to 10 M in various tumor models including ovarian, thyroid, colon, and pancreatic carcinomas (38 -40, 59).…”

Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer

“…Interestingly, proteasome activity recovers at the same rate with irreversible inhibitors as with slowly reversible inhibitors (27,36), presumably because of induction of de novo proteasome synthesis (37).…”

“…The proteasome inhibitors in clinical development have the greatest potency for the CT-L active site of the proteasome (24,27,36,38,39), but they differ in their activity against the other catalytic sites. The development of compounds with different selectivity profiles will help address the question of what combination of proteasome site inhibition provides maximal antitumor effects and the best therapeutic index.…”

“…NPI-0052 is active against a variety of tumor cell types (40,41), including primary plasma cells from bortezomib-resistant patients with multiple myeloma. When NPI-0052 and bortezomib were compared head to head in xenograft studies using the twice-weekly (days 1 and 4) bortezomib clinical-dosing schedule, the activity of the 2 compounds was comparable in a multiple myeloma model (38,42), whereas bortezomib displayed better efficacy than NPI-0052 in a prostate cancer model (36). In a disseminated lymphoma model, once-weekly bortezomib had superior efficacy to twice-weekly NPI-0052 (36,40).…”

Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure

“…In our previous study, we investigated the stability of 2b, instead of 2a due to its poor solubility in aqueous medium, and demonstrated that 2b is gradually degraded in aqueous medium, while its half-life (t 1/2 = 10 h in pH 7.4 buffer) 14b is longer than that of other β-lactone-type proteasome inhibitors (omuralide, 13 min; salinosporamide A, 56 min). 17 Furthermore, it was found that 2b is significantly unstable under biological conditions (t 1/2 = 2.3 min in serum), which might be correlated with the relatively weak cell growth inhibitory effect of 2a, because 2a can be as unstable as 2b. Thus, we planned to develop stabilized derivatives of 2a.…”