Structure−Activity Relationship Studies of Salinosporamide A (NPI-0052), a Novel Marine Derived Proteasome Inhibitor

Abstract

Salinosporamide A (1, NPI-0052) is a potent proteasome inhibitor in development for treating cancer. In this study, a series of analogues was assayed for cytotoxicity, proteasome inhibition, and inhibition of NF-kappaB activation. Marked reductions in potency in cell-based assays accompanied replacement of the chloroethyl group with unhalogenated substituents. Halogen exchange and cyclohexene ring epoxidation were well tolerated, while some stereochemical modifications significantly attenuated activity. These findings provide insights into structure-activity relationships within this novel series.

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

“…This was the result, in part, of bortezomibmediated inhibition of NF-B and expression of genes involved in cancer cell survival such as Bcl-2 family members (2). NPI-0052 (salinosporamide A), is a novel nonpeptide, marinederived proteasome inhibitor shown to display irreversible inhibition of all three enzymatic activities (CT-L, trypsin-like, and caspase-like) of the 20S proteasome core (6,7). NPI-0052 targets CT-L and trypsin-like proteolytic activity at lower concentrations than bortezomib; however, higher concentrations are required for inhibition of C-L which is predominantly affected by bortezomib (8).…”

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

“…Specifically, delineation of mechanisms mediating interaction of proteasome inhibitors with 20S proteasome will allow designing potent and therapeutically efficacious proteasome inhibitors. In this context, our recent study characterised a novel proteasome inhibitor NPI-0052, a small molecule derived from fermentation of Salinospora, a new marine Gram-positive actinomycete (Feling et al, 2003;Macherla et al, 2005;Chauhan et al, 2005a). Importantly, NPI-0052 is distinct from Bortezomib, orally bioactive, and an equipotent antitumour agent (Chauhan et al, 2005a).…”

“…However, in contrast to Omuralide, NPI-0052 has a uniquely methylated C3 ring juncture, chlorinated alkyl group at C2, and cyclohexene ring at C5 (Figure 1). Structure -activity relationship studies showed that (1) replacement of chloroethyl group with unhalogenated substituents resulted in loss of potency in cell-based assays, and (2) halogen exchange and cyclohexene ring epoxidation were well tolerated, although some stereochemical modifications markedly attenuated activity (Macherla et al, 2005). These data suggested that whereas the beta-lactone is a key pharmachophre of both Omuralide and NPI-0052, the enhanced potency of NPI-0052 is due to the substituents in bicyclic ring system.…”

“…A recent report describing the crystal structure of NPI-0052 in complex with the 20S proteasome revealed an important consequence of betalactone ring opening and a mechanism of irreversible binding vis-à-vis omuralide (Groll et al, 2006). Collectively, these structural differences account for the enhanced in vitro and in vivo potency of NPI-0052 compared to Omuralide (Feling et al, 2003;Macherla et al, 2005;Groll et al, 2006).…”

Stabilization Effect of Resin on the Production of Potent Proteasome Inhibitor NPI-0052 During Submerged Fermentation of Salinispora tropica

“…Structureactivity relationship and mechanistic studies indicated that the b -lactone ring system and the chlorine atom are required for the potent activity of NPI-0052 [3,6]. The b -lactone ring system is susceptible to hydrolysis in an aqueous environment [6,7], such as the submerged fermentation condition for the production of NPI-0052 by S. tropica. End product feedback repression of secondary metabolite biosynthesis is a well known phenomenon [8].…”