Marizomib (formerly also known as ML-858, NPI-0052 and Salinosporamide A), a naturally occurring salinosporamide with potential antineoplastic activity has been isolated from the marine actinomycete Salinospora tropica. It is a strong and selective inhibitor of the 20S proteasome (IC50 = 1.3 nM). Marizomib prevents compensatory hyperactivation in patients with solid tumors and multiple myeloma by irreversibly inhibiting the proteasome. Marizomib's capacity to cross the blood-brain barrier is its sole therapeutic action in malignant gliomas. Compared to its reversible analogs, marizomib shows longer inhibition, reduced efflux, and increased cytotoxicity.

Physicochemical Properties

Molecular Formula	C15H20CLNO4
Molecular Weight	313.7766
Exact Mass	313.108
Elemental Analysis	C, 57.42; H, 6.42; Cl, 11.30; N, 4.46; O, 20.40
CAS #	437742-34-2
Related CAS #	437742-34-2
PubChem CID	11347535
Appearance	Off-white to pink solid powder
LogP	1.408
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	4
Heavy Atom Count	21
Complexity	508
Defined Atom Stereocenter Count	5
SMILES	O=C([C@H](CCCl)[C@]1(C)O2)N[C@@]1([C@H]([C@@H]3C=CCCC3)O)C2=O
InChi Key	NGWSFRIPKNWYAO-SHTIJGAHSA-N
InChi Code	InChI=1S/C15H20ClNO4/c1-14-10(7-8-16)12(19)17-15(14,13(20)21-14)11(18)9-5-3-2-4-6-9/h3,5,9-11,18H,2,4,6-8H2,1H3,(H,17,19)/t9-,10+,11+,14+,15+/m1/s1
Chemical Name	(1R,4R,5S)-4-(2-chloroethyl)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione
Synonyms	ML 858; NPI0052; Marizomib; ML-858; NPI-0052; (-)-Salinosporamide A; ML858; NPI 0052; Salinosporamide A
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	CT-L (IC50 = 3.5 nM); CT-T-laspase-like (IC50 = 28 nM); trypsin-like (IC50 = 430 nM)
ln Vitro	Marizomib (Salinosporamide A) (0.1-10000 nM; 72 hours) effectively and dose-dependently decreases D-54 and U-251 cell survival. For D-54 and U-251, the IC50s are ≤20 nM and ～52 nM, respectively[1]. Marizomib (24 hours; 60 nM) causes apoptosis and caspase-3 activation in glioma cells[1].
ln Vivo	Marizomib (Salinosporamide A) (0.15 mg/kg; i.v; twice a week for three weeks) is associated with no toxicity and significantly reduces the growth of tumors[3].
Cell Assay	Proteasome activity is assessed in neural stem cells and glioblastoma-derived glioma stem cells at baseline and two hours following marizomib (60 nM) treatment. Using Matrigel invasion chambers, the invading potential of D-54 MG and U-251 MG cells treated or not treated with 60 nM marizomib for a 24-hour period is examined.
Animal Protocol	CB-17 SCID-male mice (4-6 weeks old)[3] 0.15 mg/kg i.v; twice a week for three weeks
References	[1]. Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brainbarrier. Neuro Oncol. 2016 Jun;18(6):840-8. [2]. Molecular mechanisms of acquired proteasome inhibitor resistance. J Med Chem. 2012 Dec 13;55(23):10317-27. [3]. Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model. Br J Haematol. 2010 May;149(4):550-9.
Additional Infomation	Salinosporamide A is a salinosporamide in which the core (1R)-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione skeleton is substituted at positions 1, 4, and 5 by (1S)-cyclohex-2-en-1-yl(hydroxy)methyl, 2-chloroethyl, and methyl groups, respectively (the 1R,4R,5S diastereoisomer). A potent proteasome inhibitor, it has attracted interest for potential use in the treatment of various cancers. It has a role as an antineoplastic agent and a proteasome inhibitor. It is a salinosporamide, an organochlorine compound, an organic heterobicyclic compound, a beta-lactone and a gamma-lactam. Marizomib has been used in trials studying the treatment of Cancer, Melanoma, Lymphoma, Glioblastoma, and Malignant Glioma, among others. Marizomib has been reported in Salinispora and Salinispora tropica with data available. Marizomib is a naturally-occurring salinosporamide, isolated from the marine actinomycete Salinospora tropica, with potential antineoplastic activity. Marizomib irreversibly binds to and inhibits the 20S catalytic core subunit of the proteasome by covalently modifying its active site threonine residues; inhibition of ubiquitin-proteasome mediated proteolysis results in an accumulation of poly-ubiquitinated proteins, which may result in the disruption of cellular processes, cell cycle arrest, the induction of apoptosis, and the inhibition of tumor growth and angiogenesis. This agent more may more potent and selective than the proteasome inhibitor bortezomib. Drug Indication Treatment of malignant glial tumours

Solubility Data

Solubility (In Vitro)

DMSO: ≥ 100 mg/mL (~318.7 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.63 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.1869 mL	15.9347 mL	31.8695 mL
	5 mM	0.6374 mL	3.1869 mL	6.3739 mL
	10 mM	0.3187 mL	1.5935 mL	3.1869 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.