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Purity: ≥98%
Delanzomib (formerly known as CEP-18770) is a novel, potent, and oral bioactive inhibitor of the proteasome's chymotrypsin-like (CL) activity that may have anti-tumor effects. With an IC50 of 3.8 nM, it inhibits the CL-proteasome with minimal effect on the proteosome's tryptic and peptidylglutamyl activities. Its significant in vivo antitumor efficacy was demonstrated in SCID mice using the human MM RPMI 8226 subcutaneous xenograft model.
| Targets |
Chymotrypsin-like activity of the proteasome (IC50 = 3.8 nM)
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| ln Vitro |
Delanzomib (CEP-18770; 20 nM; 12-24 hours) treatment causes cleaved caspases-3, -7, and -9 to gradually appear over the course of 12 to 24 hours of exposure in the human MM cell lines, RPMI-8226, and U266[1].
Delanzomib (CEP-18770; 5-40 nM; 4-24 hours) treatment induces an accumulation of ubiquitinated proteins over 4 to 8 hours[1]. Delanzomib (CEP-18770) inhibits the in vitro proliferation of endothelial cells, the development of blood vessels, and the formation of bone clots. It also exhibits a favorable cytotoxicity profile towards normal cells[1]. |
| ln Vivo |
Delanzomib (CEP-18770; 7.8-13 mg/kg; oral administration; twice a week; for 4 weeks) treatment improves overall median survival in a systemic model of human multiple myeloma (MM) and leads to a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues and complete tumor regression of MM xenografts[1].
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| Enzyme Assay |
Human multiple myeloma cells are subjected to two rounds of washing in cold phosphate-buffered saline, pelleting and lysing with one volume of glass beads (less than 106 microns, acid-washed) and an equivalent volume of homogenization buffer (50 mM Tris (pH 7.4), 1 mM dithiothreitol, 5 mM MgCl₂, 2 mM ATP, and 250 mM sucrose) by vortexing at a high speed for 15–30 minutes at 4°C. In order to extract beads, membrane fractions, nuclei, and cell debris from the supernatant, centrifugation at 16,000 g for five minutes is performed. With the Bradford assay, extracts' protein content is measured. The assay for proteasome activity is explained below. Proteins in equal amounts (usually 60 g) are electrotransferred onto polyvinylidene difluoride (PVDF) membranes after being denatured by boiling in reducing sample buffer and separated by 12.5% SDS-PAGE. Horseradish peroxidase-coupled goat or swine anti-rabbit secondary antibody and dansyl-sulfonamidohexanoyl polyclonal antibody (1:7,500, rabbit) are used in immunoblotting, which is followed by enhanced chemiluminescence.
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| Cell Assay |
In 24-well plates, HMEC and TEC cells are seeded at a density of 10⁴ cells/well in DMEM with 5% FCS supplemented. Cells are cleaned, allowed to air dry, and stained with crystal violet according to the instructions following a 48-hour incubation period with proteasome inhibitors. Using a standard curve that was created using known cell numbers, the cell number in duplicate samples is ascertained. Three duplicates of each experiment are run. On 4 × 10⁴ cells/well in DMEM supplemented with 5% FCS, the in vitro formation of capillary-like structures is investigated. Cells are washed (cells/well in 24-well plates) and seeded onto Matrigel-coated wells in DMEM containing 0.25% BSA after 48 hours of incubation with proteasome inhibitors. HMEC and TEC cells (5 × 10³ per well), suspended in 200 μL DMEM with 5% FCS (positive control), serum-free medium (negative control), are layered onto the Matrigel surface in the presence or absence of proteasome inhibitor CEP-18770. After incubating the cells for six hours at 37 °C, the cells are examined under an inverted microscope, and the experimental outcomes are noted. Data is analyzed using the Micro-Image system to determine the mean (× 1 SD) of the total length of capillary-like structures. The computer analysis system then expresses this mean as mm/field in 5 different fields at a magnification of 100 × in duplicate wells for 4 different experiments.
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| Animal Protocol |
SCID mice injected with RPMI 8226 cells[1]
7.8 mg/kg, 10 mg/kg, 13 mg/kg Oral administration; twice a week; for 4 weeks |
| References | |
| Additional Infomation |
Delanzomib is a C-terminal boronic acid peptide inhibitor which induces apoptosis in multiple myeloma, hematological and solid tumor cell lines. It has a role as a proteasome inhibitor, an apoptosis inducer and an antineoplastic agent. It is a threonine derivative, a phenylpyridine, a C-terminal boronic acid peptide and a secondary alcohol. It is functionally related to a L-threonine.
Delanzomib has been used in trials studying the treatment of Solid Tumors, Multiple Myeloma, and Lymphoma, Non-Hodgkin. Delanzomib is an orally bioavailable synthetic P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome, with potential antineoplastic activity. Delanzomib represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. The intracellular protein IkappaBalpha functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB. |
| Molecular Formula |
C21H28BN3O5
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| Molecular Weight |
413.28
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| Exact Mass |
413.212
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| Elemental Analysis |
C, 61.03; H, 6.83; B, 2.62; N, 10.17; O, 19.36
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| CAS # |
847499-27-8
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| Related CAS # |
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| PubChem CID |
24800541
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.207
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| Index of Refraction |
1.563
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| LogP |
2.89
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
30
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| Complexity |
557
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C(C1C=CC=C(C2C=CC=CC=2)N=1)(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](B(O)O)CC(C)C
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| InChi Key |
SJFBTAPEPRWNKH-CCKFTAQKSA-N
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| InChi Code |
InChI=1S/C21H28BN3O5/c1-13(2)12-18(22(29)30)24-21(28)19(14(3)26)25-20(27)17-11-7-10-16(23-17)15-8-5-4-6-9-15/h4-11,13-14,18-19,26,29-30H,12H2,1-3H3,(H,24,28)(H,25,27)/t14-,18+,19+/m1/s1
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| Chemical Name |
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]butanoyl]amino]-3-methylbutyl]boronic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (5.25 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 21.7 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: 2.17 mg/mL (5.25 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.17 mg/mL (5.25 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4197 mL | 12.0983 mL | 24.1967 mL | |
| 5 mM | 0.4839 mL | 2.4197 mL | 4.8393 mL | |
| 10 mM | 0.2420 mL | 1.2098 mL | 2.4197 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01348919 | Completed | Drug: CEP-18770 Drug: Lenalidomide |
Multiple Myeloma | Teva Branded Pharmaceutical Products R&D, Inc. |
August 3, 2011 | Phase 1 Phase 2 |
| NCT01023880 | Terminated | Drug: CEP-18770 | Multiple Myeloma | Cephalon | January 2010 | Phase 1 Phase 2 |
| NCT00572637 | Completed | Drug: CEP-18770 | Solid Tumors Lymphoma, Non-Hodgkin |
Ethical Oncology Science | November 2007 | Phase 1 |
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