Salinosporamide A [Marizomib] – Potent Proteasome Inhibitor

The 26S proteasome complex recognises polyubiquitinated proteins, which were marked for elimination by the E1, E2 and E3 ubiquitinating enzymes (see Figure). Upon recognition, unfolding and transfer of the de-ubiquitinated target protein by the 19S regulatory cap into the interior of the cylindrical 20S proteasome core particle, protein degradation is facilitated by catalytic β-subunits having nucleophilic N-terminal threonine (Thr1) residues. Although eukaryotic 20S proteasomes harbour seven different β-subunits in their two-fold symmetrical α7β7β7α7 stacked complexes, only three β-subunits per β-ring [subunits β1 (caspase-like), β2 (trypsin-like) and β5 (chymotrypsin-like)] are proteolytically active. These three β-subunits are major targets for small-molecule proteasome inhibitors.

Salinosporamide A is a novel, second-generation irreversible pan-proteasome inhibitor, characterised by a unique β-lactone γ-lactam bicyclic ring structure. It inhibits the 3 constitutive activities of the mammalian 20S proteasome (chymotrypsin-like, β5 [CT-L]); trypsin-like, β2 [T-L] and caspase-like, β1 [C-L]). Salinosporamide A is effective at nanomolar concentrations in vitro and demonstrates penetration in vivo into multiple different organs including the CNS, crossing the blood-brain barrier (BBB). Non-clinical studies have demonstrated that salinosporamide A rapidly forms a covalent chemical bond at the active enzymatic sites (β5, β2 and β1) in the proteasome resulting in irreversible inhibition at nanomolar concentrations. Extensive preclinical studies demonstrate the activity of salinosporamide A in a wide variety of hematopoietic, solid and CNS tumour models. Because of the enhanced CNS penetrating capability of salinosporamide A, given its lipophilic structure, it is especially of interest as a reagent in CNS tumour research.

Literature References:

1. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora: R.H. Feling, et al.; Angew. Chem. Int. Ed. Engl. 42, 355 (2003)
2. Discovery and development of the anticancer agent salinosporamide A (NPI-0052): W. Fenical, et al.; Bioorg. Med. Chem. 17, 2175 (2009)
3. Generating a generation of proteasome inhibitors: from microbial fermentation to total synthesis of salinosporamide a (marizomib) and other salinosporamides: B.C. Potts & K.S. Lam; Mar. Drugs 8, 835 (2010) (Review)
4. Salinosporamide natural products: Potent 20S proteasome inhibitors as promising cancer chemotherapeutics: T.A. Gulder & B.S. Moore; Angew. Chem. Int. Ed. Engl. 49, 9346 (2010) (Review)
5. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials: B.C. Potts, et al.; Curr. Cancer Drug Targets 11, 254 (2011)
6. Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors: A. Besse, et al.; Cell Chem. Biol. 26, 340 (2019)

Salinosporamide A

Salinosporamide A is a potent, irreversible inhibitor of all the 3 proteolytic activities of the mammalian 20S proteasome. β5 subunit: chymotrypsin-like (EC50 = 3.5nM); β2 subunit: trypsin-like (EC50 = 28nM); β1 subunit: caspase-like or peptidyl-glutamyl peptide-hydrolyzing (PGPH) (EC50 = 430nM). Salinosporamide A is a potent anticancer compound. It triggers apoptosis with distinct proteasome activity and mechanism of action compared to bortezomib (Velcade) (Prod. No. AG-CR1-3602). It displays a longer inhibition duration than bortezomib and shows potent antileukemic activity against bortezomib-resistant leukaemia cells.

AG-CN2-0444 (100µg, 1 mg, 5 mg, 50 mg and BULK) 

AdipoGen Life Sciences is an original Manufacturer of high-purity Salinosporamide A. BULK quantities are available from Stock!

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Originally posted by Adipogen on: https://adipogen.com/salinosporamide

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